case series

Submucosal Regrowths after Watch and Wait in Rectal Cancer: A Case Series

Ilaria Prata1*, Sofieke J D Temmink2, Shirin Shahbazi Feshtali3, Alexander L Vahrmeijer1, Stijn Crobach4, Elke E M Peters5, Jurjen J Boonstra6, Fabian A Holman1, Koen C M J Peeters1

1Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands

2Department of Surgery, Karolinska University Hospital, Stockholm, Sweden

3Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands

4Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands

5Department of Pathology, Haaglanden Medical Centre, The Netherlands

6Department of Gastroenterology, Leiden University Medical Centre, Leiden, The Netherlands

*Corresponding author: Ilaria Prata, Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands

Received Date: 16 February 2023

Accepted Date: 20 February 2023

Published Date: 22 February 2023

Citation: Prata I, Temmink SJD, Feshtali SS, Vahrmeijer AL, Crobach S, et al (2023) Submucosal Regrowths after Watch and Wait in Rectal Cancer: A Case Series. Ann Case Report. 8: 1180. DOI:


This article aims to create awareness about the possibility of submucosal regrowth in neoadjuvant-treated rectal cancer patients managed non-operatively as a new alternative to the far more common intraluminal regrowth’s. Additionally, it highlights the important role of MRI in the follow up of these patients. Three patients who achieved a complete clinical response (cCR) after neoadjuvant (chemo) radiotherapy developed a rectal cancer regrowth in the submucosal layer without any signs of intraluminal disease. These regrowth’s were primarily diagnosed by MRI including diffusion-weighed imaging (DWI) whereas concomitant endoscopy and digital rectal examination did not reveal any regrowth. All three patients were operated and the presence of an adenocarcinoma in the rectal wall was confirmed by pathological analysis. Although uncommon, these cases show that a regrowth can occur in the submucosal layer, while being undetectable in the lumen. Importantly, MRI played a fundamental role in diagnosing these regrowth’s at a very early stage.

Keywords: Magnetic Resonance Imaging (MRI); Non- Operative Management; Regrowths; Submucosa; “Watch and Wait”


In the past years organ-preserving management of rectal cancer has become increasingly popular. The Watch and Wait (W&W) strategy as an alternative to surgical resection for rectal cancer derives from the preliminary study of Angelita Habr-Gama[1] and its clinical relevance has internationally been supported by multiple studies in the years thereafter [2-6]. The main goal of this approach is to preserve the rectum and subsequently prevent the surgery-related complications that can occur in up to 35% of operated patients. Rectal cancer surgery is associated with mortality as well as with short and long term complications that can permanently affect patients’ quality of life [7]. In the Netherlands, patients with stage II (T3cd-4 N0) and III (T any N1-2) rectal cancer are treated with neoadjuvant (chemo) radiotherapy (nCRT), according to either the national guidelines or prospective trials [8]. In particular, patients with stage II rectal cancer are commonly offered Short- Course radiotherapy (SCRT, 5 x 5 Gy) followed by subsequent resection or delayed surgery as it has been shown to reduce the risk of recurrences and increase long-term survival compared to surgery alone [8-10]. On the other hand, stage III patients with high-risk morphological characteristics (mesorectal fascia involvement, extramural vascular invasion (EMVI) or extramesorectal disease) are treated pre-operatively with long course chemo radiotherapy (LCCRT, 25 x 2 Gy + concomitant twice-daily capecitabine 825 mg/m2) in order to reduce the tumour volume and increase the rate of R0 resections [8]. Based on the evaluation of the response to pre-operative treatments, patients with residual tumour are operated with Total Mesorectal Excision (TME) while those with a clinical complete response (cCR) enter a strict follow up protocol according to the principles of W&W, nowadays still exclusively offered in the context of clinical studies. Surveillance after cCR consists of periodic digital rectal examination (DRE), rectoscopy and magnetic resonance imaging (MRI) [6,11-14]. In more recent years, MRI is increasingly being used together with diffusion- weighed imaging (DWI) [3,15]. Combined, these investigations are aimed at early detection of potential regrowth’s. Although most patients achieving a cCR experience a sustained response over time, between 15 to 30% [1,2,11,13,16,17] of patients develop a regrowth, most likely in the first 2 to 3 years of follow up [11,13,16,17]. Traditionally, a regrowth is diagnosed in the rectal lumen although mesorectal and more rarely pelvic regrowth’s have also been described in literature [11,13]. In this article, we discuss three patients who were successfully treated with nCRT for rectal cancer. After achieving a cCR, all three patients were managed non-operatively and developed a submucosal regrowth during follow up. Interestingly, no signs of regrowth were visible in the rectal lumen. All three patients are included in the Wait and See Trial (registered as NCT03426397) and one patient is registered in the International Watch and Wait Database (IWWD). The Wait and See Trial is an ongoing Netherlands and Belgium-wide prospective observational study including patients with any stage, pathology-confirmed, primary rectal cancer who have achieved cCR after undergoing neoadjuvant LCRCT or SCRT with delay. All included patients are evaluated for response to nCRT with DRE, endoscopy and MRI 1.5 or 3.0 Tesla including DWI. Follow up lasts 5 years and consists of periodic DRE, carcinoembryonic antigen (CEA) measurements, rectoscopy and MRI. Additionally, for the first 3 years total-body CT scans are performed to exclude distant metastases. The IWWD is an international registry that collects retrospective and prospective data of patients who have not been operated for a rectal cancer of any stage after neoadjuvant treatment, irrespective of the type of treatment and of the reason why surgery has been omitted. Collected data is used to provide better understanding of the risks, benefits and outcomes of W&W approaches, both oncological and functional. The database is coordinated by the Clinical Research Centre of the Leiden University Medical Centre (LUMC) [18].

Case Specifics

Three patients have been treated in the Leiden University Medical Centre (LUMC) in Leiden, the Netherlands, between March 2019 and December 2020. The LUMC is a tertiary referral centre for organ preservation strategies in rectal cancer patients.

Case 1

Firstly, we present a 43-year-old woman who was diagnosed with a cT3N1M0 rectal adenocarcinoma. The patient had a history of Irritable Bowel Syndrome and rectal bleedings that were neglected for years and were eventually investigated with a colonoscopy. Among the three removed polyps, only a rectal semi-circular lesion of 4 cm at a distance of 8.5 cm from the anorectal junction was malignant. The histological analysis reported a well differentiated, mismatch repair proficient (MMRp) adenocarcinoma. At the time of diagnosis the tumour reached the perirectal fat, one mesorectal node had malignant features, no distant metastases were detected in the thorax and abdomen and CEA was <1 mcg/l. The patient received SCRT (5 x 5 Gy) followed by re-assessment after 7 weeks after the end of radiotherapy, according to the schedule presented in the Stockholm III trial [10]. At the time of restaging, both the MRI and the endoscopy showed a non-suspicious scar at the former location of the tumour, CEA was 0.8 mcg/l, while DRE was difficult to perform given the location of the original tumour. For that reason, it has been decided together with the patient to proceed with a non-operative management according to the W&W principles. Six months after the end of radiotherapy, both the rectoscopy and the MRI confirmed a cCR. At nine months follow up, the MRI described a small hyperintense rectum wall thickening with diffusion restriction, while the rectoscopy reported a sustained cCR. This finding was confirmed by the MRI performed three months later (Figure 1a and b), at which time the rectoscopy confirmed the presence of an intraluminal regrowth (Figure 1c and d). After discussing the case within the multidisciplinary panel and with the patient, it was agreed to perform a laparoscopic Low Anterior Resection (LAR). Surgery was well tolerated and no major complications arose. However, symptoms as pain, fatigue and alteration of the defecation patterns in terms of consistence, frequency and urgency persisted for months. The pathology report on the surgical specimen confirmed the presence of a well differentiated ypT2N0 rectal adenocarcinoma, without (lymph) vascular invasion (Figure 1e). The most relevant interventions and investigations are summarised in chronological order in Figure 2.


Figure 1: Patient 1. (a) T2 transversal Multicoil MRI image and (b) DWI MRI image from the MRI investigation that identified the submucosal regrowth (white arrows). Endoscopic images taken during (c) the last rectoscopy that confirmed a cCR and (d) the rectoscopy performed at the time of radiological detection of a submucosal regrowth. (e) H&E stained slide showing a slightly irregular, but non-dysplastic mucosal surface and fibrosis of the submucosal stroma, extending in the muscular wall. The low- grade intestinal adenocarcinoma is situated in the muscular wall reaching up to, but not infiltrating the perimuscular fat tissue. The tumour is sharply demarcated and not surrounded with abundant desmoplastic stroma or lymphocytic infiltrate. There is no associated (lympho) vascular invasion or perineural invasion. cCR = clinical Complete Response; DWI = Diffusion Weighed Imaging; H&E = Haematoxylin and eosin.


Figure 2: Patient 1. Timeline of the most relevant interventions and investigations. SCRT = Short Course Radiotherapy; cCR = clinical Complete Response; W&W = Watch and Wait

Case 2

The second patient is a man aged 50 years without comorbidities. Because of rectal bleedings and an alteration of defecation patterns, a MRI was performed that led to the diagnosis of a cT3N1M0 rectal cancer without high risk characteristics at 6 cm distance from the anal verge. At the time of diagnosis, the colonoscopy showed multiple polyps in the colon and confirmed the presence of a rectal adenocarcinoma and CEA was 3.2 mcg/l. Given the characteristics and the stadium of the tumour, this patient received SCRT with delay. Eleven weeks after the completion of SCRT, the rectoscopy reported a cCR while on MRI images a non-specific residual thickening of the rectal wall was described. Therefore, the multidisciplinary panel suggested to prolong the waiting period and the MRI performed at 15 weeks after the end of SCRT also confirmed the cCR. Thirteen months after the completion of SCRT, the MRI report described a small rectal wall thickening that grew into the mesorectal fat tissue with hyperintense T2 signal and diffusion restriction (Figure 3a and b), compatible with a regrowth that was not visible at the concomitant rectoscopy. Based on the results of the MRI, an echo-endoscopy- guided biopsy was performed within three weeks (Figure 3c and d) and pathological examination of the biopsy confirmed presence of malignant cells. The CEA at the same time point was 2.4 mcg/l, which did not differ from the previous measurement. Agreement was found among the multidisciplinary panel and the patient for laparoscopic LAR, which caused no major complications. The pathological report described a ypT3N0 rectal adenocarcinoma. However, no alteration of the rectal mucosa was visible at macroscopical evaluation of the surgical specimen. The most relevant interventions and investigations are summarised in chronological order in Figure 4.