Mucinous adenocarcinoma aggravated by long-standing solitary rectal ulcer syndrome: a rare case report

doi:10.21203/rs.3.rs-2585182/v1

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Mucinous adenocarcinoma aggravated by long-standing solitary rectal ulcer syndrome: a rare case report

https://doi.org/10.21203/rs.3.rs-2585182/v1

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Solitary rectal ulcer syndrome (SRUS) is a chronic infrequent rectal lesion, but SRUS canceration can be found in specific cases. Currently, there is no definite diagnosis for this anomaly. The following is the case of a 29-year-old male patient with long-standing SRUS, who rapidly developed progression to mucinous adenocarcinoma within 5 years. Colonoscopy and pathological examination confirmed the diagnosis of SRUS mucinous adenocarcinoma. Immunohistochemical analysis showed the positive expression in MLH1(+), MSH2(+), MSH6(+), PMS2(+), HER2(+). FOLFOX6 chemotherapy followed by surgery is effective for controlling SRUS-related mucinous adenocarcinoma progression, during the follow-up for the first 2 years. This article suggests that clinicians should pay close attention to canceration in patients with SRUS to improve patient outcomes.

solitary rectal ulcer syndrome

mucinous adenocarcinoma

colonoscopy

immunohistochemical test

surgery

prognosis

Solitary rectal ulcer syndrome (SRUS) is an uncommon and chronic disorder of defecation with the period of remission and relapse. The combination of histological features, clinical manifestations, and endoscopic characteristics forms the cornerstone of diagnosis for SRUS(Gouriou et al., 2021). It has an estimated incidence of 1/100 000 per year and commonly affects young adults. Among SRUS patients, 40% of them were found with ulcers, 20% with solitary ulcer and the rest have various shapes and sizes of the lesions, from hyperemic mucosa to broad-based polypoid(Zhu, Shen, Qin, & Wang, 2014). SRUS is always recognized as a chronic benign inflammatory disorder with characteristics including rectal bleeding, diarrhea, constipation, and anorectal pain(J.-M. Chiang, C.-R. Changchien, & J.-R. Chen, 2006). Patients usually complain of bleeding or mucoid discharge per rectum when defecting, also associated with feelings of tenesmus, obstructed defecation, incontinence, or sensation of incomplete evacuation(D’Hoore, 2017). There are few case reports describing SRUS with a possibility of turning into cancer. What’s more, the occurrence of mucinous adenocarcinoma is even rarer, and very little is known about its diagnosis, treatment, and outcome. Therefore, we reported this specific case of SRUS-related mucinous adenocarcinoma.

In 2018, a 29-year-old male patient was evaluated at a local hospital for a 5-year history of constipation with no symptoms of myxoid discharge or rectal bleeding. The patient denied any significant past medical history or relevant family history. In 2019, the colonoscopy of health examination was suggestive for rectal ulcer to the patient. However, Mesalazine Suppositories treatment was shown to be useless for the patient on the advice of the local doctor. To further evaluate and treat the disease, he visited the Peking Union Medical College Hospital (PUMCH). Then, he was highly suspected as SRUS but without definitive diagnosis at that time, due to lack of histopathological evidence. From July 2019 to November 2020, the patient repeatedly presented with fever, accompanied by pain in the right buttocks without obvious inducement. After treatment with cephalosporin antibiotics, these symptoms were relieved but easily reoccurred. In November 2020, the patient returned to PUMCH again for reexamination and further treatment. Colonoscopy showed a huge ulcerative lesion in the rectum. A large, deep concave lesion was observed, measuring 3×5 cm in length, about 1/3 to 1/2 of the annulus cavity in depth on the rectum and 6 cm proximal to the anal verge. The discomfort symptoms including fever and right buttocks pain were relieved by transverse colostomy in December 2020. Unfortunately, four months after the surgery, the patient reappeared these symptoms with limited lower limb movement in severe condition, which can only be effectively alleviated by anti-infective therapy. In August 2021, the MRI examination of the patient revealed multiple intestinal wall defects in the middle, upper rectum and surrounding abscesses of the defects. The lesion extended between the left gluteus medius and gluteus minimus. Bone marrow edema of the sacrum was found. Local edema of bilateral piriformis muscle and left gluteus maximus muscle were possible. There were multiple lymph nodes in mesangial area of rectum and sigmoid colon and both pelvic walls, some of which were enlarged.

For further treatment, the patient was admitted to our hospital, the sixth affiliated hospital of Sun yat-sen university. The endoscopic and pathological evaluation suggested the diagnosis of SRUS, accompanied with presacral tumor in the rectum (Fig. 1). Considering the large tumor size and deep tumor invasion, only the ulceration mucosa over the mass was identified this time by colonoscopy biopsy. The computerized tomography (CT) scan showed a larger presacral tumor and enlarged fistula, which suggested the possibility of neoplastic lesions. And Magnetic resonance imaging (MRI) revealed the presacral tumor is mainly consisted of mucus, with the main part 44mm×75mm×107mm. (Supplementary Fig. 1). After discussion and evaluation, the patient underwent surgery for the presacral tumor resection. Tumor location was at arterial sacral, about 1/3 to 1/2 of the annulus cavity in depth and on the rectum 4–7 cm proximal to the anal verge. The size of the tumor was 5 × 4 × 3 cm, with grayish-yellow appearance grossly. The tumor was slightly tender, jelly-like quality, with grayish-white cut surface. 4 grayish-white vesicle-like tissues were found in the tumor, with a bunch of mesenteric tissues (7 × 3 × 2 cm) (Fig. 2). Besides, the immunohistochemical test of pathological tissue showed the positive expression in MLH1(+), MSH2(+), MSH6(+), PMS2(+), HER2(+) (Fig. 3). The patient was thus diagnosed as presacral mucinous adenocarcinoma with no lymph node metastasis.

Moreover, the patient also underwent the genetic testing. The chromosome copy map was shown in supplementary material. (Supplementary Fig. 2) It showed the tumor mutational burden (TMB) value of 4.91 mut/Mb, microsatellite instability (MSI) of 0.13%, and copy number variation (CNV) of 0.02%, ranking in prior 23.5% of mucinous adenocarcinoma patients. The PD-L1 immunohistochemical test was shown to be negative. About 1 month after the surgery, the patient received 8 courses of FOLFOX6 postoperative adjuvant chemotherapy, accompanied with three kinds of traditional anti-colorectal cancer drugs, oxaliplatin, leucovorin and fluorouracil. And pelvic radiotherapy started on September 17th 2021, IMRT GTV55Gy/25f, CTV45Gy/25f. No special discomfort was observed during radiotherapy. Postoperative MR scanning showed the rectum was partially absent and the sigmoid stump was normal. (Supplementary Fig. 3) The patient recovered well without any special complications during the following 2 years. We obtained the consent from the patient for publication of this report.

In this study, we reported a specific SRUS patient who rapidly developed progression to mucinous adenocarcinoma within 5 years. The disease was diagnosed through colonoscopy and pathological examination. Moreover, the immunohistochemical test of pathological tissue showed positive expression in MLH1(+), MSH2(+), MSH6(+), PMS2(+), HER2(+). FOLFOX-6 chemotherapy followed by surgery was effective for controlling SRUS-related mucinous adenocarcinoma progression during the follow-up of the first 2 years.

In clinic, SRUS is rare and often misdiagnosed, due to misleading by the macroscopic appearance and unfamiliarity with the histological features of SRUS. Most SRUS are benign, slowly progressive form of rectal bleeding, diarrhea, constipation, and anorectal pain. But rare malignant cancers can be reported. Unfortunately, we still do not know the exact mechanism of SRUS, but several hypotheses exist. It is widely believed that SRUS results from repeated mucosal trauma with the ischemia of the rectal wall from straining at defecation. Additionally, occult or overt rectal prolapse and paradoxical contraction of the pelvic muscles are associated with the SRUS development, which can lead to ischemia and ulceration. It is even less clear why SRUS turned into canceration. It has been revealed that more than 95% of colorectal cancer are adenocarcinomas.(Zhuang et al., 2012) Mucinous adenocarcinoma is the well-differentiated and rarest histologic subtype. Meanwhile, the greater risk of colorectal cancer in ulcerative colitis (UC) patients is well demonstrated. It has been showed that, the risk of colorectal cancer increases 8 or 10 years after the diagnosis of UC.(Yashiro, 2014) Chronic inflammation and the increased turnover of epithelial cells of the UC patients contribute to the development of cell dysplasia, which is further related with colorectal cancer. Meanwhile, the development of colorectal cancer in UC patients is also associated with reactive oxygen species (ROS) generation, activation of Wnt/β-catenin pathway and intestinal microbiome dysfunction.(Rogler, 2014) Scattered studies have briefly reported SRUS transformation to adenocarcinoma with a low incidence rate.(Abid et al., 2012; Ball et al., 2005; J. M. Chiang, C. R. Changchien, & J. R. Chen, 2006; Lambin et al., 2022; Li & Hamilton, 1998; Tsuchida et al., 1998) One of the most representative studies reported 116 SRUS cases from a single-center of Pakistan from 1990 to 2011 and only 2 colonic adenocarcinomas were observed, with the canceration rate 1.72%.(Abid et al., 2012)

Colonoscopy is the first line procedure for diagnosing SRUS. Ours and related research have found that the SURS patients with mucinous adenocarcinoma exhibit several common features, including abundant muco-purulent exudates, Kudo pit pattern, and vascular pattern intensity. However, most of SRUS canceration are nonspecific, which can be easily misdiagnosed as presacral tumor. In the research of Shuan and his team, after six times biopsy examination, three patients were finally diagnosed as primary rectal adenocarcinoma from 6 initial-SRUS-diagnosis patients.(Li & Hamilton, 1998) Moreover, recent studies found two particularly remarkable features of SURS related mucinous adenocarcinoma, fibromuscular obliteration and distorted glandular architectures.(J. M. Chiang et al., 2006; Tsuchida et al., 1998) Several research showed that up to 38% SRUS patients are accompanied with similar changes of sessile serrated polyps, which appears to act as a unique pathway to colorectal carcinogenesis.(Ball et al., 2005) Without exception, these studies together with ours, indicate the significance and necessity of the precise method to detect SRUS canceration as early as possible.

Results of immunohistochemical test revealed the positive expression of related proteins, MLH1(+), MSH2(+), MSH6(+), PMS2(+), HER2(2+). All of the five proteins belong to the mismatch repair (MMR) system. In clinic, the consensus is that tumors lacking MLH1, MSH2, PMS2, or MSH6 expression were considered as dMMR, whereas tumors that expressed MLH1, MSH2, PMS2, or MSH6 were considered pMMR.(Fink, Aebi, & Howell, 1998) MLH1, MSH2, MSH6 and PMS2 genes encode proteins that mediate DNA mismatch repair.(Jiricny, 2006) In detail, MLH1 protein has been reported to be associated with the progress that hyperplastic-type polyps evolve into DNA microsatellite unstable cancers of colorectal.(Iino et al., 1999) MSH2, functions in identifying mismatches and participating in DNA repair and MSH2 deficiency has been reported to enhance cancer susceptibility for the association of hereditary nonpolyposis colorectal cancer.(Qiu et al., 2021) The MSH6 protein provides instructions for producing proteins which play an essential role in repairing DNA. It can join with MSH2 protein to form a two-protein complex called a dimer, which identifies locations on the DNA where errors have been made during DNA replication.(Cederquist et al., 2004) Moreover, the PMS2 protein helps fix errors made during DNA replication in preparation for cell division. It joins with MLH1 protein to coordinate the activities of other proteins that repair the errors, made during DNA replication. The repairs are performed by removing DNA sections containing error and replacing them with corrected DNA sequence.(Gill et al., 2005) And HER2 is strongly associated with promoting carcinogenesis in clinic.(Vranić, Bešlija, & Gatalica, 2021) However, due to the tumor heterogeneity and individual differences of patients, these genes have certain reference significance in differentiating SRUS canceration to malignant mucinous adenocarcinoma. The copy number changes of chromosomes can provide tumors with raw material for evolution.

Some research had reported the worse prognosis for mucinous colonic adenocarcinoma patients, compared to the patients with non-mucinous colonic adenocarcinoma(Maisano et al., 2012; Ott et al., 2018). However, any specific treatment for mucinous adenocarcinoma in patients with SRUS has been unknown. Currently, the main clinical therapy for colorectal adenocarcinoma includes surgery, immunotherapy, targeted molecular therapy, traditional chemotherapy etc.(Luo, Cen, Ding, & Wu, 2019) Nowadays, surgical resection, radiotherapy, and chemotherapy are the mainstay for colorectal adenocarcinoma treatment. In our case, the patient underwent presacral tumor resection and pelvic partial rectal resection followed by FOLFOX6 chemotherapy. FOLFOX-6 has emerged as effective alternative regimens for the first-line treatment of metastatic colorectal cancer(Ducreux et al., 2011). The modified FOLFOX-6 regimen has been regarded commonly as the adjuvant chemotherapy, after the resection for patients with colorectal cancer(Nguyen et al., 2019). After 2 years of clinical follow-up, the prognosis of this patient is good, without local recurrence or distant metastasis. This case illustrates that surgery plus FOLFOX6 chemotherapy is effective for controlling SRUS-related mucinous adenocarcinoma, as well as generates guiding significance to clinical diagnosis and treatment.

In conclusion, this case highlights the fact that colonoscopy with pathological confirmation is a reliable method to diagnose SRUS and its canceration. Early-stage SRUS-related mucinous adenocarcinoma can be successfully treated by surgery combined with FOLFOX6 chemotherapy, leading to improved patient outcomes and survival. It is hoped that this article will increase the understanding of SRUS and provide guidelines for the diagnosis and treatment of SRUS canceration.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author Contributions

QT-R and CQ-L conceived the idea. JX-Z, HJ and CQ-L wrote draft of the manuscript. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.

Funding

This work was supported by the National Natural Science Foundation of China (No.81903294), and Medical Scientific Research Foundation of Guangdong Province of China (A2021123), and Guangzhou Basic and Applied Basic Research Foundation (202102020120).

Acknowledgments

We are thankful to The Sixth Affiliated Hospital of Sun Yat-sen University, and the patient for this rare case.

Data Availability Statement

Data described in the manuscript, code book, and analytic code will be made available upon request.

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Table 1. The timeline table for the patient

Timeline	Diagnosis	Examination or Treatment
2019	Rectal ulcer	Mesalazine Suppositories treatment
July 2019 - November 2020	Rectal ulcer	Cephalosporin antibiotics
November 2020	Rectal ulcer
December 2020	Rectal ulcer	Transverse colostomy
August 2021 September 2021	Solitary rectal ulcer syndrome (SRUS); Mucinous adenocarcinoma	Colonoscopy Presacral surgery; FOLFOX6 chemotherapy

No competing interests reported.

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Mucinous adenocarcinoma aggravated by long-standing solitary rectal ulcer syndrome: a rare case report

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