Imaging and Management of Rectal Cancer

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Imaging and Management of Rectal Cancer Supreeta Arya MD, DMRD, DNB Consultant Radiologist;Expert Opinion;5Cnetwork;Ex-Professor;Member , Saugata Sen MD Consultant Radiologist , Reena Engineer MD Convener;Professor , Avanish Saklani MS, FRCS Associate Professor , Tarun Pandey M.D, F.R.C.R Professor;MSK/MRI-Body imaging Fellowship Director PII: DOI: Reference:

S0887-2171(20)30007-X https://doi.org/10.1053/j.sult.2020.01.001 YSULT 903

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Seminars in Ultrasound CT and MRI

Please cite this article as: Supreeta Arya MD, DMRD, DNB Consultant Radiologist;Expert Opinion;5Cnetwork;Ex-Pr Saugata Sen MD Consultant Radiologist , Reena Engineer MD Convener;Professor , Avanish Saklani MS, FRCS Associate Professor , Tarun Pandey M.D, F.R.C.R Professor;MSK/MRI-Body imaging Imaging and Management of Rectal Cancer, Seminars in Ultrasound CT and MRI (2020), doi: https://doi.org/10.1053/j.sult.2020.01.001

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1 TITLE Imaging and Management of Rectal Cancer AUTHORS 1. Supreeta Arya, MD, DMRD, DNB Consultant Radiologist, Expert Opinion, 5Cnetwork Ex-Professor, Radio-diagnosis, Tata Memorial Centre Mumbai, India Member, Expert Committee, National Cancer Grid, India [email protected]

2. Saugata Sen, MD Consultant Radiologist Department of Radiology and Imaging Sciences Tata Medical Center Kolkata 700160, INDIA [email protected]

3. Reena Engineer, MD Convener, GI Disease management group Professor, Radiation Oncology Department of Radiation Oncology Tata Memorial Hospital Mumbai 400012, INDIA [email protected] 4. Avanish Saklani , MS, FRCS Associate Professor Department of Surgical Oncology Robotic & Colorectal Surgery Tata Memorial Hospital Mumbai 400012, INDIA Email: [email protected] 5. Tarun Pandey M.D, F.R.C.R Professor of Radiology and Orthopedics MSK/MRI-Body imaging Fellowship Director University of Arkansas for Medical Sciences Little Rock, AR 72205 USA 501-526-5052 [email protected]

CORRESPONDING AUTHOR

2 Supreeta Arya, MD, DMRD, DNB Consultant Radiologist, Expert Opinion, 5Cnetwork Ex-Professor, Radio-diagnosis, Tata Memorial Centre Mumbai, India Consultant Radiologist, National Cancer Grid, India [email protected] Address: 12 A Ivanhoe, General Bhosale Marg, Mumbai -400021, INDIA Abstract High-resolution phased array external MRI is the first investigation of choice in rectal cancer for local staging, both in the primary and restaging situations. Use of MRI helps differentiate between those with good prognosis, which can be offered upfront surgery and the poor prognostic cases where treatment intensification is needed. MRI identified poor prognostic factors are threatened or involved mesorectal fascia, T3 tumors with > 5mm extramural spread, those with extramural vascular invasion, pelvic sidewall nodes and mucinous tumors. At restaging, use of MRI helps evaluate response and an MR tumor regression grading system is being evaluated. Complete response seen on clinical examination and endoscopy, needs confirmation on MRI using both T2 weighted and diffusion-weighted sequences to justify a “watch and wait” approach. In this subset of patients, MRI also plays a role in monitoring and detecting early regrowth. In those with partial response, MRI helps define surgical margins and can be used as a roadmap to decide between sphincter preserving surgeries and radical sphincter sacrificing surgeries; pelvic exenteration and pelvic sidewall lymph node dissection. Poor responders on MRI may benefit from adjuvant chemotherapy. Use of MRI thus helps in individualizing treatment in rectal cancer. Key words: rectal cancer, management, primary staging, restaging, structured report, watch and wait, tumor regression grade

3 Introduction Imaging has an essential role in evaluating rectal cancer for staging, planning therapeutic strategy, evaluating treatment response, in surgical planning and in follow-up. In the last decade, there has been better understanding of the disease leading to further refinement in treatment as well as imaging. Consistent with this, there has been a growing body of literature in imaging of rectal cancer [1-5]. The purpose of the article is to review contemporary literature and guidelines to present the latest concepts in imaging of rectal cancer.

Learning Objectives This article will address the following objectives in rectal cancer: 

Management principles including role of various imaging methods in staging

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Optimal MRI technique for local staging specified by various guidelines

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Key anatomical concepts to understand loco-regional staging

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Current concepts in the role of MRI in primary local staging

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Current concepts in the role of MRI in restaging after neo-adjuvant treatment

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Structured reporting templates for staging and restaging

Role of Imaging, Staging and Stage-based management Knowledge of management principles can help the clinical radiologist to better understand the role of imaging and be more effective in practice. Treatment of rectal cancer is dependent on the stage of the disease that is decided by several loco-regional risk factors. Local recurrence and distant metastases are the two challenges while planning therapy. Pre-therapeutic identification of poor prognostic factors helps select cases for treatment intensification while the early cases are spared the morbidity of radical therapy.

4 Diagnosis of rectal cancer begins with history and physical examination including DRE (digital rectal examination), endoscopy/ office-based proctoscopy followed by biopsy and histopathology (HP). ESMO (European Society of Medical Oncology) guidelines also recommend measurement of serum CEA (carcino-embryonic antigen) levels in a proven case [6]. Ideally imaging is ordered after a HP diagnosis while in practice at times it may be performed before the biopsy report arrives.

Once the diagnosis of rectal cancer is established, guidelines recommend that management should be decided by a multidisciplinary team (MDT); consisting of radiologists, surgeons, radiation oncologists, medical oncologists and pathologist. Tumor staging is required and is done using the current AJCC 8th edition [7] shown in Table 1. Staging prefix of ‘c’, ‘y’ and ‘p’ represent respectively the clinical stage (that is based on both clinical and radiological information), the pathological stage (after HP) and post neo-adjuvant therapy stage (at restaging). The first imaging investigation ordered for primary clinical staging would be a CT thorax and abdomen for metastatic status (M category) along with pelvic MRI (highresolution with phased array coil) for loco-regional staging. Only in a few select cases, PETCT may be added for the distant metastatic workup: a) in established hepatic metastases to rule out extrahepatic disease when radical surgery is planned b) when metastases are suspected but not confirmed on CT c) when CEA is very high at presentation & d) when MRI reveals extensive extramural vascular invasion (EMVI) which is an adverse prognostic factor for distant metastases [6].

Metastatic rectal cancer translates to AJCC stage IV A-C (depending on M1a to M 1c categories) and is treated with both curative and palliative intents [6]. Non-metastatic rectal cancer has been variously classified for treatment purposes by various guidelines in the

5 United States, UK and Europe. In the United States, treatment is according to NCCN guidelines (Table 2), which is based on TNM staging [8]. ESMO divides it into early, intermediate, locally advanced & advanced disease; while the UK NICE guidelines divides it into low, intermediate and high-risk disease [6,9]. The information required for these stratifications is based on loco regional staging derived from imaging (Table 2), mostly from pelvic MRI with information from Endorectal Ultrasound (ERUS) used to identify the very early cases alone.

Multidetector CT has been evaluated for locoregional staging and in early studies compared poorly with MRI for T category, sphincter evaluation and mesorectal fascia (MRF) invasion that is needed to decide the circumferential resection margin (CRM) status, especially in low anterior rectal tumors [10-11]. However recently, for high and mid rectal cancers especially, there have been few retrospective studies with favorable reports using CT for local staging [12-14]. A retrospective study using new generation multi-detector CT scanner reported high accuracy for MRF invasion using both axial as well as multi-planar reformations (MPR) [12]. Another study using multi-slice CT reported high accuracy for T category (85.7%) [13]. CT alone without MRI was considered sufficient as a useful screening tool at baseline to select poor prognosis rectal cancers for neo-adjuvant therapy, in a scenario of limited MRI availability [14]. However the use of contrast enhanced CT abdomen and pelvis for pretreatment loco regional staging of rectal cancer is considered appropriate by the American college of Radiology only if MRI cannot be performed and tumor is locally advanced. Moreover a contrast enhanced CT abdomen and pelvis study caries a relative radiation level exposure of 10-30 mSV per study [15]. Low-dose CT with iterative reconstruction algorithm showed high quality images for evaluation of MRF invasion with significant radiation dose reduction in another study [16]. Nevertheless, both ESGAR and SAR guidelines advocate

6 MRI as mandatory and technique of first choice for both local staging and restaging of rectal cancer with the exception of very early tumors that can undergo local excision [17-18]. Hence currently the accepted routine role of CT (thorax and abdomen ± pelvis) is in the metastatic workup of rectal cancer.

The limitation of MRI in differentiating T1 from T2 tumors is well known while ERUS can identify and stratify T1 tumors with high accuracy [19-20]. Sessile T1 cancers have been further subclassified based on the depth of submucosal invasion into 3 subcategories. In this subclassification, the submucosal layer is divided into three layers according to the depth; upper third, middle third and lower third [21]. T1 tumors are categorized according to the depth of submucosal invasion respectively as sm1, sm2 and sm3 [22]. Hence when contemplating transanal endoscopic microsurgery (TEM) for very early rectal cancer (cT1, sm1, cN0), it is important to add ERUS to MRI [6]. Additional criteria for TEM includes moderately or well differentiated tumors < 3 cm, location within 8cm of anal verge, and involving less than 30% of wall circumference [8,23]. After TEM, if histology shows adverse features or reveals a T1 sm ≥ 2, a total mesorectal excision (TME) surgery is performed, with/ without perioperative CRT [6]. ERUS though has no role in locally advanced cancers as it has many limitations, chief being in identifying the MRF and lateral pelvic wall nodes [24-25].

T2 tumors are offered TME surgery, the standard treatment that involves resection of the rectum along with the mesorectal fat (containing nerves, vessels and nodes) up to the mesorectal fascia and an ideal specimen should not breach the MRF [6,8]. The caudal extent of surgery depends on the location and extent of disease spread and can vary from low anterior resection to abdominoperineal excision (APE) and extralevator APE (ELAPE) to pelvic exenteration (Table 3).

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T3 tumors are currently sub classified into T3 a, b, c and d according into the extent of extramural spread beyond muscularis propria (Table 1) [17-18]. In the United states T3 and higher tumors are treated with neo-adjuvant chemoradiotherapy (CRT) prior to restaging and surgical treatment [8]. The aim of CRT is to decrease the size and stage of the tumor so that resectability becomes feasible and risk of local recurrence is reduced. In Europe however, while T3c/d and T4b tumors are treated with neo-adjuvant CRT followed by surgery; T3 a and T3b tumors without other adverse features such as MRF invasion are considered intermediate risk and treated with TME without neo-adjuvant CRT [6]. The Canadian (Quicksilver) trial using MRI to identify T3a & b to offer upfront surgery, found a low rate of CRM positivity [26]. Neo-adjuvant CRT is less recommended for tumors above the peritoneal reflection and tumors > 12cm from the anal verge, as it does not improve prognosis of these cancers [27]. Radiation planning depends on the loco-regional extent of involvement and includes the lateral pelvic wall nodes if involved/ suspicious, the criteria for which are discussed later [6,8].

Restaging MRI (yMRI) is routinely recommended in guidelines and performed to evaluate response [6,17-18]. The timing of the restaging MRI and the interval to surgery is debated. Traditionally the recommended interval time for both was 6- 8 weeks from the completion of neo-adjuvant CRT [6,8,17]. Restaging MRI is also useful for surgical planning and defining resection margins. T3 tumors with clear MRF would require a standard TME [6,8-9]. The lateral pelvic wall nodes are not addressed in a standard TME surgery and require additional dissection if the response to radiation is poor (nodal criteria discussed later) [28-30]. T4b tumors would require more radical surgeries beyond TME with pelvic exenteration (removal

8 of adjacent organs) [31]. In patients with poor response to neo-adjuvant CRT, adjuvant chemotherapy can be offered with reports of increased resectability to the extent of 62% [32].

In contrast to the above, 10-23 % of patients have been described to undergo pathological complete response (pCR) in the TME specimen after neo-adjuvant CRT raising the possibility of organ preservation in rectal cancer [33-34]. Retrospective studies have also shown that a slightly longer interval of 8-12 weeks between completion of CRT and restaging MRI results in higher pCR rate [35]. Studies with induction/consolidation chemotherapy prior to standard neo-adjuvant CRT (called total neo-adjuvant therapy) have also reported a higher pCR rate [36]. The organ preservation approach also called the “watch and wait” can be adopted when a tumor shows complete clinical response to CRT. Careful patient selection and patient consent is required for this strategy and requires use of valid diagnostic methods to establish complete response in the primary tumor and nodes. Currently the standard method is to use a combination of DRE, flexible sigmoidoscopy and MRI using both standard T2-weighted images and diffuse –weighted imaging (DWI). Lastly MRI has a role in the follow-up of those on the organ preservation protocol and is useful for detection of early regrowth that could be treated with local excision [33]. Use of MRI in the management of rectal cancer can therefore help in individualized treatment.

MR imaging recommendations High-resolution MRI examination performed with standardized imaging protocol is of utmost importance to obtain good quality images that can help accurate loco-regional staging necessary for optimal treatment. The hardware, the sequences, slice thickness, the preparation used and the contraindications have been summarized in Table 4. The rectal MRI protocol

9 used at our institute is shown in Table 5. The information obtained from imaging has to be conveyed precisely in a ‘structured report’ that has been recommended in guidelines [17-18].

Major anatomical landmarks on MRI The radiologist needs to be familiar with key anatomical landmarks in order to accurately stage the tumor and help plan optimal therapy. The structures that need to be recognized are enumerated below in relation to the spread of tumor in various directions.

Craniocaudal extension For evaluating the cranio-caudal extent of tumor, location of the anal verge (AV) is important (Figure1A). The rectum extends from the AV to a distance 15 cm cranially and can be divided into upper rectum (10.1-15cm from AV), mid rectum (5.1-10cm from AV) and lower rectum (0 to 5 cm from AV). Measurement of the tumor length and its distance from anal verge corresponds to measurement as with flexible sigmoidoscopy (Figure1 A).

The anorectal junction (ARJ) and the anorectal ring (Figure1B) are synonymous. The ring is a muscular structure felt by the surgeon during a DRE and is formed by the upper border of puborectalis and upper border of internal anal sphincter and this corresponds to the junction of anal canal and rectum [37-38]. The anal canal that can measure between 3- 5cm is located within the lower rectum extending from AV to ARJ (Figure1B).

The upper limit of the rectum (the rectosigmoid junction) is a subject of controversy with only 30% using the distance from AV as the landmark and 35% using the anterior peritoneal reflection [39]. An alternative useful landmark proposed is the sigmoid take off, a point where the rectum leaves the sacral curve to continue forward as the sigmoid colon (Figure1C). It is

10 also the point where the sigmoid mesocolon ends and the mesorectum begins. Identifying the sigmoid take off does not require radiological expertise and is therefore a practical landmark. Any tumor below this point of take off is a rectal tumor and would require MRI for staging [40].

Lateral extension The lateral spread of the tumor through the walls of the rectum and into the mesorectum and beyond is reflected in the T category and evaluating this requires recognition of the layers of the rectal wall (Figure 2A). The mesorectum filled with fat and containing vessels and nodes surrounds the rectum and anteriorly is seen only below the anterior peritoneal reflection. The mesorectal fascia is an important landmark to decide the circumferential surgical resection margin of TME (Figure 2A) and to identify cases with high risk for local recurrence.

Far laterally along the lateral pelvic sidewall, internal iliac and obturator nodes need to be identified (Figure 2B). The obturator nodes are located medial to the obturator internus muscle and lateral to the internal iliac artery along the obturator artery. The internal iliac nodes are situated medial to the internal iliac artery at the level of obturator internus muscle [41]. These are locoregional nodes for rectal cancer while the external iliac nodes are nonlocoregional.

Anterior extension Anteriorly infiltrating tumors can invade the anterior peritoneal reflection as it drapes over the dome of the bladder and top of seminal vesicles in the male and over the uterine fundus in the female to insert into the rectum along its anterior surface in the upper and mid third (Figure 3). The rectogenital septum or Denonvillier’s Fascia is seen below the anterior

11 peritoneal reflection (Figure 4) and in continuity with it and in close proximity with the anterior mesorectal fascia, and continues further into the perineal body below. In the males the septum separates the mesorectum from the prostatic capsule [42].

Posterior extension Posteriorly the tumor can extend into the retrorectal space (Figure 4A) and reach the presacral fascia that lines the anterior surface of the sacrum. The presacral fascia continues anteriorly and laterally as the pelvic parietal fascia that lines the entire pelvic cavity.

Inferior extension Tumor extension into the infralevator compartment can involve the sphincter complex. The levator ani muscle that forms the pelvic floor is like a hammock on both sides of the mesorectum. Its most distal attachment is at the puborectalis near the anorectal junction. Posteriorly its proximal attachment is to the tip of the coccyx (Figure 5). It has fixed attachment on both sides to the ischial spine. In the infralevator compartment when tumor involves low rectum, extension can occur into the sphincter complex (Figure 5) comprising of the internal sphincter, intersphincteric space and external sphincter [42].

Local staging using pretreatment MRI Prior to reading the MRI examination, the radiologist needs to check the patient’s medical records for the DRE and endoscopy reports, the pathology report and for any previous treatments or procedures. After reading the MRI, a structured report should be generated that gives information on the tumor location, its morphology, T category, MRF status, anal sphincter complex, N category and EMVI. A detailed structured reporting template for primary staging is shown in Figure 6.

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Location & Morphology The tumor location was traditionally specified as distance of lower limit of tumor from AV and its presence in the lower, mid and upper rectum with maximum cranio-caudal length [43]. The distance of inferior border of tumor from the ARJ was recorded as well. The latest ESGAR and SAR guidelines specify that the circumferential location from o’clock to o’clock position should also be routinely reported. The tumor morphology also needs description (template in Figure 6). Particular note is to be made whether tumor is mucinous or nonmucinous as the former have far worse prognosis with high tendency to metastasize [17-18]. Mucinous tumors have very bright stromal signal on T2-weighted sequences (Figure 7). MRI identified mucinous adenocarcinoma is an independent imaging biomarker for poor prognosis [44].

T category and pitfalls The Al Sukhni meta-analysis showed the sensitivity, specificity and accuracy of MRI for T category assessment as 87%, 75% and 85% [45]. T category is decided by noting the deepest invasive portion of the tumor that often overlies a central ulcerated area [26]. 2D T2-weighted sequences are > 80% accurate for differentiating between T2 and T3 tumors [17], but inadequate to differentiate between T1 and T2 tumors. DWI-MRI is neither accurate to differentiate between T1 and T2 tumors nor between T2 and T3 tumors [17].

The ESGAR guidelines recommend routine reporting of T3 subcategories (a-d) based on the extent of extramural extension (Figures 8-9) into the mesorectal fat (Table 1). The basis of this stratification is that tumors with > 5mm extramural spread (T3c/T3d) have poor prognosis

13 (with survival dropping from 85% to 54%) even though the MRF may not be threatened or involved [46] and hence require treatment intensification.

Limitation though may arise in differentiating between T2 and T3a tumors (<1mm extramural spread) and the reason is spiculation into the perirectal fat that could either be tumor or desmoplastic reaction. Most overstaging and understaging is known to occur between T2 and T3 tumors. A solution to this dilemma is to regard fine low signal intensity spicules as fibrosis (T2) while intermediate signal intensity thicker spicules or broad based lesion extensions (into the mesorectal fat) as tumor (T3) (Figure 10)[27].

T4b tumors are those that invade adjacent organs, which may display a change in signal intensity similar to the rectal tumor (Figure 11). Recent guidelines clarify that invasion of the pelvic sidewall muscles, pelvic floor, bone, nerves or ureter also qualify as T4b [4,17-18]. All involved structures need mention as this has a bearing on therapy planning. Invasion of the anterior peritoneal reflection is T4a and has to be confirmed on both axial and sagittal images (Figure 12).

CRM (MRF) status and issues The shortest distance between the primary tumor and MRF decides the CRM status. The concept of CRM relates to the surgical resection margin in TME. It has been therefore suggested that the term “CRM” is inappropriate when used preoperatively and appropriate only when used postoperatively [47]. Instead preoperatively the MRF status has to be described. If the tumor to MRF distance is < 1mm, MRF is involved or positive (Figure 13) while a tumor to MRF distance of 1-2 mm is a threatened MRF. Stranding reaching into the MRF is also considered positive status. An involved MRF implies poor prognosis and

14 requires treatment intensification. It is to be noted that invasion of the MRF is considered a T3 tumor and not T4 [17].

MRI has a high specificity of 94% for ruling out MRF involvement [43]. 2D T2-weighted sequences are accurate for deciding involved and uninvolved MRF while DWI-MRI sequences are inadequate [17]. Previously proximity of a node, deposit or EMVI to the MRF was considered for deciding the MRF status [48]. Shihab in a series of 396 patients noted that involvement of the MRF by nodes is uncommon [49]. Current guidelines no longer consider these as criteria to decide MRF status. However presence of suspicious nodes, deposits or EMVI close to the MRF still needs to be described in the report for meticulous surgical planning [4,17-18].

Low rectal cancer and sphincter invasion The mesorectum tapers in the lower rectum and the fat is much less in thickness as compared to mid and high rectum leading to higher likelihood of MRF invasion. In the lower rectum at a level above the level of anorectal junction, the MRF too thins out as it approaches the levator and the MRF status at this level is decided by measuring the shortest distance of the tumor to the levator muscle.

In addition when rectal cancer is located in or extends into the lower third, the sphincter complex needs careful attention. Involvement of the sphincter complex usually qualifies for neo-adjuvant CRT before definitive surgery. Although the internal anal sphincter (IAS) is continuation of the circular muscle of the rectum, tumor invasion of the IAS is T3 [17], while in the upper and mid third, invasion of the muscular layer is T2. Hence radiologists must not apply the conventional AJCC T category in the low rectum but instead record invasion of the

15 IAS, intersphincteric space, external anal sphincter and the levator [Figure 14]. In addition it would be useful to specify the caudal extent of sphincter invasion, ie disease extension into the proximal third, mid third or lower third of the sphincter complex [17-18]. Such detailed information helps in deciding whether intersphincteric resection is feasible or if radical ELAPE has to be offered.

Another situation arises when rectal cancer is situated entirely in the anal canal. Below the inferior limit of the levator (where it inserts into the upper border of puborectalis), the lower part of the low rectum (from ARJ to the AV) lies within and is synonymous with the anal canal. Staging tumor arising in this region requires knowledge of the histology, whether adenocarcinoma (rectal) or squamous cancer (usually anal canal) as both these are treated differently. Rectal adenocarcinoma as discussed is treated with neo-adjuvant CRT and surgery while squamous cancers respond well to definitive chemo-radiotherapy and seldom require surgery [4]. Inguinal nodes are included in the radiation planning when rectal cancer extends within 3 cm of the anal verge [4].

Nodal category The diagnostic accuracy of MRI for N category has been lower than for T category [45]. New criteria have been proposed for nodal characterization into metastatic nodes (N+) and these are based on nodal size and morphology (Table 6) and guidelines recommend routine use of these. Nodal characterization relies on 2D T2-weighted images. DWI-MRI is not accurate to differentiate N+ and N0 nodes [17]. The new nodal criteria are useful for characterizing mesorectal nodes, but can be used for extramesorectal nodes too. The AJCC 8th edition classifies N category into N0, N1 and N2 based on number of nodes (Table 1) but does not specify location. However, nodal location impacts therapy planning and needs mention. While

16 mesorectal nodes are addressed in the standard TME, the pelvic sidewall nodes that do not respond to radiation need additional dissection. The pelvic sidewall nodes include a) obturator nodes and b) internal iliac nodes and are loco-regional for rectal cancer. Ogura et al found that there was a higher rate of lateral recurrence in those with pelvic sidewall nodes >7mm in short axis despite receiving neoadjuvant chemoradiation and TME [50]. Hence all pelvic sidewall nodes >7mm in short axis in the pretreatment setting, especially when rounded and heterogeneous are considered involved (Figure 15A). External iliac nodes are nonlocoregional nodes and are located along the external iliac vessels and cranial to the inguinal ligament. These are rarely involved and are usually ovoid or elongated in shape [4]. Other regional nodes in rectal cancer are superior rectal, sigmoid and inferior mesenteric, presacral (Figure 15B), lateral sacral and nodes at the sacral promontory.

Extramural vascular Invasion (EMVI) Microscopic as well as macroscopic spread of tumor into the perirectal vasculature reduces disease free and overall survival and is associated with both distant metastases and local recurrence [3,51]. EMVI is visualized as intermediate signal of tumor replacing the vessel flow void; as enlargement of the vessel and irregularity of its contour [48](Figure 16). MRI has high specificity (96%) in identifying macroscopic EMVI (on the T2-weighted images and not on DWI) and can be used for treatment intensification [48,51-52].

Extranodal Tumor Deposits (ENTDs) Another category in the AJCC 8th edition is N1c, classified as presence of tumor deposits in the subserosa, mesentry or nonperitonealized perirectal tissues, yet not clearly understood. ENTD is a pathological term defined as tumor nodules without histological evidence of residual lymph node or identifiable vascular or neural structures [7]. A meta-analysis of 26

17 studies showed that ENTDs have prevalence between 10 -44% and are associated with poorer overall survival. An association between ENTDs and EMVI has also been reported [53]. On imaging, ENTD is seen as a nodule with irregular contour in the meosrectum [54]. However on imaging it is difficult to differentiate between a metastatic node with extranodal spread and an ENTD [3,53]. ENTDs from mucinous tumors may have low contrast with mesorectal fat on T2-weighted images and be obscured and adding noncontrast T1-weighted sequences may prove very useful, as mucin is hypointense (Figure 7B).

Restaging MRI (yMRI) after neoadjuvant CRT In the restaging setting, the radiologist should study the patient medical records prior to reporting the MRI for a) treatment received and b) results of the post therapy DRE and endoscopy records. Ideally comparison with pretreatment imaging should be performed. Reading a restaging MRI is along the same lines as for the primary staging and a structured report is recommended (Figure 17). The diagnostic performance of restaging MRI is lower than in the primary staging (Table 7) [55]. Good response to neo-adjuvant therapy may result in down staging and downsizing; poor response is seen as unchanged signal intensity and dimensions (Figure 18) and progression is seen as increase in bulk and likely invasion of adjacent organs. The parameters to be studied on restaging MRI are described below.

Tumor length In good response, distance of the lower limit of the tumor from the AV increases while the cranio-caudal tumor extent decreases (Figure 19). Tumor length has remained the most practical metric for change in tumor size at restaging as compared to volumetry, which has not found universal favor [17].

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yT category The tumor thickness and extramural spread may decrease (Figure 20A &B) with decrease in the T category and subcategory.

yN category Nodes may disappear or decrease in size. Their margins may show fragmentation and the contour may become flattened. The signal intensity may become low/dark due to fibrosis (Figure 20 C & D). However nodal criteria have not been defined in the restaging setting and only rely on size [17]. All nodes ≥ 5mm are considered malignant (yN+) while nodes < 5mm are considered benign (yN0). Support for this criterion with respect to lateral pelvic sidewall node, is noted from the study by Ogura A et al. In a series of 780 patients, the nodal size decreased from 7mm or greater on the primary MRI to 4mm or less on the restaging MRI in 30% cases and in these patients, lateral lymph node dissection could be avoided [56]. Persistently enlarged nodes herald a high risk of local recurrence.

However since restaging MRI may not accurately identify the yT and yN stage (Table 7), formal categorization of these in the restaging template is being questioned with some preferring to describe the presence or absence of residual tumor instead.

yMRF status A fat pad appearing between tumor and MRF suggests clearing of the MRF invasion (Figure 21 A & B). However persistent stranding reaching the MRF is equivocal [17]. If the tumor retracts completely from the MRF with subtle fibrotic stranding towards the MRF it may also suggest a clear MRF [57]. Persistent intermediate or isointense signal intensity tumor at the

19 MRF carries a 90% risk of positivity. A completely fibrotic MRF at restaging has a 50% risk of residual tumor at HP (Figure 21C) [57].

Sphincter status Restaging MRI may demonstrate freeing of the intersphincteric space and is reported to have high diagnostic performance to predict feasibility of successful sphincter preservation [58].

yEMVI Improved disease free survival has been reported when regression in EMVI is seen on the post neoadjuvant CRT restaging MRI [59]. Persistent EMVI at restaging might benefit from adjuvant chemotherapy prior to surgery [60]. Guidelines recommend that EMVI should be routinely reported at restaging as well [17].

Qualitative response Response can also be reflected in qualitative changes seen as 1) Fibrosis, seen as very low signal intensity (while residual tumor shows intermediate signal). A completely low signal fibrotic residue without any intermediate signal intensity mass is considered as complete or near complete response (Figure 21) while a normal threelayered rectal wall is indicative of complete response [17]. 2) Intermediate signal intensity non-mucinous tumors sometimes respond by mucinous degeneration (Figure 22 A, B), which does not indicate adverse prognosis [1,2]. The mucin shows very bright signal on T2W images. 3) Mucinous tumors usually are poor responders to CRT and may not show any change in signal intensity or size (Figure 18). Occasionally they can respond and develop acellular

20 mucin on HP. However the cellular and acellular mucin cannot be differentiated on imaging [61]. 4) The unaffected rectal walls may show diffuse submucosal edema (Figure 22C).

MRI Tumor Regression Grade The above changes at restaging MRI require comparison with pretreatment staging for confident interpretation. Response to preoperative CRT can also be assessed using tumor regression grade on restaging MRI [62]. This was originally the basis of response assessment at HP on the specimen after surgical resection. The relative amounts of viable tumor, fibrosis, necrosis and inflammation were compared [4] and classified on a Tumor Response Grade (TRG) scale (0-4 0r 1-5) in various systems like Mandard [63] and Dworak[64] . Since high – resolution MRI has the capability of superior soft tissue resolution, attempts were made to extrapolate this grading system to MRI to evaluate it as an imaging biomarker for treatment response. Table 8 shows the 5-point MRI tumor regression grade scale (mrTRG) that solely relies on T2-weighted sequences and does not use DWI-MRI (Figures 23-25). High diagnostic accuracy for predicting complete response and survival outcomes has been reported for mrTRG in few studies [62,65], but the results could not be uniformly reproduced [66, 67]. The TRIGGER trial (ongoing) will evaluate mrTRG as a novel biomarker to stratify response [68]. Lee et al proposed a modified mrTRG by incorporating DWI findings [69] and an mrTRG system was also proposed for mucinous tumors [70].

The structured report of the restaging MRI should preferably describe the tumor response; in particular if complete/ near complete response is seen or whether residual disease is suspected [1,18]. This may be more useful than trying to assign a formal yT/yN category.

21 Imaging in “watch and wait”: value of DWI With the advent of “watch and wait” organ preservation strategy in rectal cancers undergoing complete clinical response, the need for imaging to reliably assist prediction of complete pathological response has become imperative. The current standard approach is a combination of DRE and endoscopy (accurate for the assessment of the luminal response) and MRI with T2-weighted and diffusion weighted sequences [33]. FDG-PET and ERUS have been evaluated, but currently MRI is the best imaging method to assess response of the primary tumor and the nodes [71]. The pitfall with MRI is in distinguishing post CRT fibrosis from viable tumor. Addition of DWI to T2 weighted MRI for predicting primary tumor response significantly improves performance with sensitivity increasing to 84% when using both as compared to 50% when using T2-weighted sequences alone [55]. DWI MRI images are to be routinely assessed visually by examining the high b value diffusion images and the ADC maps and not with quantitative ADC measurements [17]. Residual tumor shows high signal on the high b value image and dark signal on the ADC map (Figures 25-26). Fibrosis shows dark signal on both b value images and ADC maps (T2 dark through effect). T2 shine through effect seen as high signal on both set of images is due to small pools of luminal fluid; it may also be seen in mucinous tumors making DWI less effective in these tumors (Figure 7C) [57]. To assess nodal status, the best method is T2 weighted MRI and complete disappearance of the nodes is the most certain criterion. DWI may not be able to differentiate between yN+ and yNo nodes [17]. Pitfalls with DWI include artifacts such as susceptibility artifacts due to luminal gas that cause pile up of signal that could be mistaken as tumor [57].

Summary Table 9 summarizes the changes/additions in the staging system and imaging guidelines for rectal cancer in pretreatment and restaging scenarios since 2018. Management of rectal cancer

22 today is a multidisciplinary effort. The advances in rectal cancer imaging enable the radiologist to play a pivotal role in assisting optimal management in both the primary and restaging settings. Structured reporting templates help convey information precisely. The information obtained from imaging can help offer personalized treatment in rectal cancer.

23 References

1. Horvat N, Carlos Tavares Rocha C, Clemente Oliveira B, et al. MRI of Rectal Cancer: Tumor Staging, Imaging Techniques, and Management. Radiographics. 2019 ; 39(2):367-387. 2. Horvat N, Petkovska I, Gollub MJ.MR Imaging of Rectal Cancer. Radiol Clin North Am. 2018; 56(5): 751-774. 3. Brown PJ, Hyland R, Quyn AJ, et al. Current concepts in imaging for local staging of advanced rectal cancer. Clin Radiol. 2019 ;74 (8):623-636. 4. Gollub MJ, Lall C, Lalwani N, Rosenthal MH.Current controversy, confusion, and imprecision in the use and interpretation of rectal MRI. Abdom Radiol (NY). Abdom Radiol (NY). 2019 May 6. doi:10.1007/s00261-019-01996-3. 5. Kalisz KR, Enzerra MD, Paspulati RM.MRI Evaluation of the Response of Rectal Cancer to Neoadjuvant Chemoradiation Therapy. Radiographics. 2019 ;39(2):538556. 6. Glynne-Jones R, Wyrwicz L, Tiret E, et al. ESMO Guidelines Committee.Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 ;29(Supplement_4):iv263. 7. M.B. Amin, S.B. Edge, F.L. Greene, et al, (Eds.) AJCC cancer staging manual. 8th ed. Springer, New York; 2017 8. Benson AB, Venook AP, Al-Hawary MM, et al. Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018 ; 16(7):874-901. 9. NICE.Clinical guideline.Colorectal cancer:the diagnosis and management of colorectal.2011. https://www.nice.org.uk/guidance/cg131

24 10. Vliegen R, Dresen R, Beets G, et al. The accuracy of Multi-detector row CT for the assessment of tumor invasion of the mesorectal fascia in primary rectal cancer. Abdom Imaging. 2008; 33(5): 604-10. 11. Maizlin ZV, Brown JA, So G, et al. Can CT replace MRI in preoperative assessment of the circumferential resection margin in rectal cancer? Dis Colon Rectum. 2010; 53(3): 308-14. 12. Ippolito D, Drago SG, Franzesi CT, et al. Rectal cancer staging: Multidetector-row computed tomography diagnostic accuracy in assessment of mesorectal fascia invasion.World J Gastroenterol. 2016 ; 22(20):4891-900. 13. Zhou XC, Chen QL, Huang CQ, et al. The clinical application value of multi-slice spiral CT enhanced scans combined with multiplanar reformations images in preoperative T staging of rectal cancer.Medicine (Baltimore). 2019; 98(28):e16374. 14. Ortega CD, Rocha MS. CT Staging to Triage Selection of Patients With PoorPrognosis Rectal Cancer for Neoadjuvant Treatment. AJR. 2019; 213(2):358-364. 15. Expert Panel on Gastrointestinal Imaging:, Fowler KJ, Kaur H, Cash BD, et al. ACR Appropriateness Criteria® Pretreatment Staging of Colorectal Cancer.J Am Coll Radiol. 2017 ; 14(5S):S234-S244. 16. Ippolito D, Drago SG, Talei Franzesi CR, et al. Diagnostic value of fourth-generation iterative reconstruction algorithm with low-dose CT protocol in assessment of mesorectal fascia invasion in rectal cancer: comparison with magnetic resonance.Abdom Radiol (NY). 2017 ; 42(9):2251-2260. 17. Beets-Tan RGH, Lambregts DMJ, Maas M, et al. Magnetic resonance imaging for clinical management of rectal cancer: Updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol. 2018 (4):1465-1475.

25 18. Gollub MJ, Arya S, Beets-Tan RG, et al. Use of magnetic resonance imaging in rectal cancer patients: Society of Abdominal Radiology (SAR) rectal cancer disease-focused panel (DFP) recommendations 2017. Abdom Radiol (NY). 2018; 43(11):2893-2902. 19. Puli SR, Bechtold ML, Reddy JB, Choudhary A, Antillon MR, Brugge WR. How good is endoscopic ultrasound in differentiating various T stages of rectal cancer? Meta-analysis and systematic review. Ann Surg Oncol. 2009; 16(2): 254-65. 20. Bipat S, Glas AS, Slors FJ, Zwinderman AH, Bossuyt PM, Stoker J. Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging--a meta-analysis. Radiology. 2004; 232(3): 773-83. 21. Kikuchi R, Takano M, Takagi K, et al. Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum. 1995; 38 : 1286–1295. 22. Maeda K, Koide Y, Katsuno H. When is local excision appropriate for "early" rectal cancer? Surg Today. 2014; 44(11): 2000-14. 23. Willett CG, Compton CC, Shellito PC, Efird JT. Selection factors for local excision or abdominoperineal resection of early stage rectal cancer. Cancer. 1994: 1; 73 (11): 2716-20. 24. Beets-Tan RG, Beets GL. Local staging of rectal cancer: a review of imaging. J Magn Reson Imaging. 2011; 33 (5):1012-9. 25. Kav T, Bayraktar Y. How useful is rectal endosonography in the staging of rectal cancer? World J Gastroenterol. 2010;16 (6):691-7. 26. Kennedy ED, Simunovic M, Jhaveri K, et al. Safety and Feasibility of Using Magnetic Resonance Imaging Criteria to Identify Patients With "Good Prognosis" Rectal Cancer Eligible for Primary Surgery: The Phase 2 Nonrandomized QuickSilver Clinical Trial. JAMA Oncol. 2019. doi: 10.1001/jamaoncol.2019.0186. [Epub ahead of print]

26 27. User’s Guide for the Synoptic MRI report for Pre-operative Staging of Rectal Cancer 2018. 28. Fujita S, Mizusawa J, Kanemitsu Y, et al; Colorectal Cancer Study Group of Japan Clinical Oncology. Mesorectal Excision With or Without Lateral Lymph Node Dissection for Clinical Stage II/III Lower Rectal Cancer (JCOG0212): A Multicenter, Randomized Controlled, Noninferiority Trial.Ann Surg. 2017; 266(2): 201-207. 29. Kusters M, Uehara K, Velde CJHV, Moriya Y.Is There Any Reason to Still Consider Lateral Lymph Node Dissection in Rectal Cancer? Rationale and Technique. Clin Colon Rectal Surg. 2017 ; 30(5):346-356. 30. Yamaguchi T, Konishi T, Kinugasa Y, et al. Laparoscopic Versus Open Lateral Lymph Node Dissection for Locally Advanced Low Rectal Cancer: A Subgroup Analysis of a Large Multicenter Cohort Study in Japan. Dis Colon Rectum. 2017 S; 60(9):954-964. 31. Waters PS, Peacock O, Warrier SK, et al. Evolution of pelvic exenteration surgeryresectional trends and survival outcomes over three decades. Eur J Surg Oncol. 2019: S0748-7983 (19) 30552-9. doi: 10.1016/j.ejso.2019.07.015. [Epub ahead of print] 32. Engineer R, Ostwal V, Arya S, et al. Additional chemotherapy and salvage surgery for poor response to chemoradiotherapy in rectal cancers. Asia Pac J Clin Oncol. 2017;13(4):322-328. 33. Beets GL, Figueiredo NF, Beets-Tan RG. Management of Rectal Cancer Without Radical Resection. Annu Rev Med. 2017 ; 68:169-182. 34. van der Valk MJM, Hilling DE, Bastiaannet E, et al and the IWWD Consortium. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018 ; 391(10139):2537-2545.

27 35. Sloothaak DA, Geijsen DE, van Leersum NJ, et al; Dutch Surgical Colorectal Audit. Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg. 2013 ;100(7):933-9. 36. Petrelli F, Trevisan F, Cabiddu M, et al. Total Neoadjuvant Therapy in Rectal Cancer: A Systematic Review and Meta-analysis of Treatment Outcomes. Ann Surg. 2019. doi: 10.1097/SLA.0000000000003471. 37. Shank B, Enker WE, Flam MS. Gross and Microscopic Anatomy. Holland-Frei Cancer Medicine. 6th edition. Hamilton, ON: BC Decker. 2003.https://www.ncbi.nlm.nih.gov/books/NBK13638/. 38. Milligan E, Morgan CN, Jones LE, Officer R. Classic Articles in Colonic Rectal Hemorrhoids (Reprinted From Lancet, Vol 2, Pg 1150-1213, 1934). Dis Colon Rectum.1985; 28:620–628. 39. T.P. McMullen, Easson AM, Cohen Z et al., The investigation of primary rectal cancer by surgeons: current pattern of practice, Can. J. Surg. 48 (1) (2005) 19. 40. D'Souza N, de Neree Tot Babberich MPM, Lord A, et al. Surg Oncol. 2018 ; 27(3):521-525. The rectosigmoid problem. 41. McMahon CJ, Rofsky NM, Pedrosa I. Lymphatic metastases from pelvic tumors: anatomic classification, characterization, and staging. Radiology. 2010;254 :31–46. 42. Brown G. Magnetic Resonance Imaging of the rectum. In Rectal Cancer: Modern approaches to treatment. Chang GJ. Springer International Publishing AG 2018 43. Beets-Tan RG, Lambregts DM, Maas M, et al. Magnetic resonance imaging for the clinical management of rectal cancer patients: recommendations from the 2012 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol. 2013; 23(9): 2522-31.

28 44. Yu SK, Chand M, Tait DM, Brown G. Magnetic resonance imaging defined mucinous rectal carcinoma is an independent imaging biomarker for poor prognosis and poor response to preoperative chemoradiotherapy. Eur J Cancer. 2014;50(5):920-7. 45. Al-Sukhni E, Milot L, Fruitman M, et al. Diagnostic accuracy of MRI for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol. 2012 ; 19(7):2212-23. 46. Taylor FG, Quirke P, Heald RJ, et al; MERCURY study group. Preoperative highresolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study. Ann Surg. 2011; 253(4):711-9. 47. Glimelius B1, Beets-Tan R, Blomqvist L, et al. Mesorectal fascia instead of circumferential resection margin in preoperative staging of rectal cancer. J Clin Oncol. 2011;29(16):2142-3. 48. Nougaret S, Reinhold C, Mikhael HW, Rouanet P, Bibeau F, Brown G. The use of MR imaging in treatment planning for patients with rectal carcinoma: have you checked the "DISTANCE"? Radiology. 2013; 268(2): 330-44. 49. Shihab OC, Quirke P, Heald RJ, Moran BJ, Brown G.Magnetic resonance imagingdetected lymph nodes close to the mesorectal fascia are rarely a cause of margin involvement after total mesorectal excision. Br J Surg. 2010;97(9):1431-6. 50. Ogura A, Konishi T, Cunningham C, et al; Lateral Node Study Consortium. Neoadjuvant Chemoradiotherapy With Total Mesorectal Excision Only Is Not Sufficient to Prevent Lateral Local Recurrence in Enlarged Nodes: Results of the Multicenter Lateral Node Study of Patients With Low cT3/4 Rectal Cancer.J Clin Oncol. 2019 ;37(1):33-43.

29 51. Schaap DP, Ogura A, Nederend J, et al. Prognostic implications of MRI-detected lateral nodal disease and extramural vascular invasion in rectal cancer. Br J Surg. 2018;105(13):1844-1852. 52. Prampolini F, Taschini S, Pecchi A, et al. Magnetic resonance imaging performed before and after preoperative chemoradiotherapy in rectal cancer: predictive factors of recurrence and prognostic significance of MR-detected extramural venous invasion. Abdom Radiol (NY). 2018 Nov 27. doi: 10.1007/s00261-018-1838-z. [Epub ahead of print] 53. Lord AC, D'Souza N, Pucher PH, et al.Significance of extranodal tumour deposits in colorectal cancer: A systematic review and meta-analysis. Eur J Cancer. 2017 ;82:92102. 54. Taylor FGM, Swift RI, Blomqvist L, Brown G. A systematic approach to the interpretation of preoperative staging MRI for rectal cancer. American Journal of Roentgenology.2008; 191: 1827–1835. 55. van der Paardt MP, Zagers MB, Beets-Tan RG, Stoker J, Bipat S. Patients who undergo preoperative chemoradiotherapy for locally advanced rectal cancer restaged by using diagnostic MR imaging: a systematic review and meta-analysis. Radiology. 2013 ;269(1):101-12. 56. Ogura A, Konishi T, Beets GL, et al; Lateral Node Study Consortium. Lateral Nodal Features on Restaging Magnetic Resonance Imaging Associated With Lateral Local Recurrence in Low Rectal Cancer After Neoadjuvant Chemoradiotherapy or Radiotherapy. JAMA Surg. 2019 :e192172. 57. Lambregts DMJ, Boellaard TN, Beets-Tan RGH. Response evaluation after neoadjuvant treatment for rectal cancer using modern MR imaging: a pictorial review. Insights Imaging. 2019 Feb 13;10(1):15.

30 58. Krdzalic J, Maas M, Engelen S, et al. MRI can accurately predict sphincter preservation after chemoradiation. Insights Imaging. 2017;8(Suppl 1):S187. 59. Chand M, Swift RI, Tekkis PP, Chau I, Brown G. Extramural venous invasion is a potential imaging predictive biomarker of neoadjuvant treatment in rectal cancer. Br J Cancer. 2014 ; 110(1):19-25. 60. Chand M, Rasheed S, Heald R, et al. Adjuvant chemotherapy may improve diseasefree survival in patients with rectal cancer positive for MRI-detected extramural venous invasion following chemoradiation. Colorectal Dis. 2017 ;19(6):537-543. 61. Wnorowski AM, Menias CO, Pickhardt PJ, Kim DH, Hara AK, Lubner MG. MucinContaining Rectal Carcinomas: Overview of Unique Clinical and Imaging Features. AJR. 2019 Apr 17:1-9. 62. Patel UB, Taylor F, Blomqvist L, et al. Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience. J Clin Oncol. 2011; 29(28):3753 63. Mandard AM, Dalibard F, Mandard JC, et al.Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994 ;73(11):2680-6. 64. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis. 1997;12(1):19-23. 65. Rengo M, Picchia S, Marzi S, et al. Magnetic resonance tumor regression grade (MRTRG) to assess pathological complete response following neoadjuvant radiochemotherapy in locally advanced rectal cancer. Oncotarget. 2017 ;8(70):114746-114755.

31 66. Hanly AM, Ryan EM, Rogers AC, et al ; MERRION Study Group. Multicenter Evaluation of Rectal cancer ReImaging pOst Neoadjuvant (MERRION) Therapy. Ann Surg. 2014; 259(4):723-7. 67. Gollub MJ, Blazic I, Felder S, et al. Value of adding dynamic contrast-enhanced MRI visual assessment to conventional MRI and clinical assessment in the diagnosis of complete tumour response to chemoradiotherapy for rectal cancer. Eur Radiol. 2019;29(3):1104-1113. 68. Battersby NJ, Dattani M, Rao S, et al. A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial.Trials. 2017 ;18(1):394. 69. Lee MA, Cho SH, Seo AN, et al. Modified 3-point MRI-based tumor regression grade incorporating DWI for locally advanced rectal cancer. AJR Am J Roentgenol. 2017;209 :1247–1255. 70. Park SH, Lim JS, Lee J et al (2017) Rectal mucinous adenocarcinoma: MR imaging assessment of response to concurrent chemotherapy and radiation therapy—a hypothesis generating study. Radiology 2017;285:124–133 71. Maffione AM, Marzola MC, Capirci C, Colletti PM, Rubello D.Value of (18)F-FDG PET for Predicting Response to Neoadjuvant Therapy in Rectal Cancer: Systematic Review and Meta-Analysis. AJR Am J Roentgenol. 2015; 204(6):1261-8.

32 Figure Legends

Figure 1.A & B. Sagittal T2W MRI. Arrows in A & B show the anal verge (AV). A. * shows the hyperintense rectal tumor, vertical white line shows the distance of the lower limit of tumor from the AV, dashed black lines depict measurement of length of tumor as with sigmoidoscopy. B. R = rectum, P = prostate, dashed horizontal line shows the anorectal junction at the level of a line joining apex of prostate to tip of coccyx. The vertical white line shows the length of the anal canal. C. Axial T2W MRI shows the sigmoid take off (arrows) where the rectum transitions into the sigmoid colon. Tumors below this level are rectal tumors while tumors proximal to this point are sigmoid colon tumors.

33

Figure 2. Axial T2W MRI A. shows the 3 layers of the rectal wall: hypointense innermost collapsed mucosa (long white arrow), hyperintense submucosa (dotted white arrow) & outermost hypointense muscularis (dashed white arrow). Rectum is surrounded by mesorectum (*) and limited by the mesorectal fascia (short white arrows). B. White arrow shows an enlarged rounded heterogeneous left obturator node medial to obturator internus muscle (dashed arrow), arrowhead shows external iliac vessels and * represents a right ovarian cyst.

34

Figure 3. A Sagittal T2W MRI (male) B. Axial T2W MRI (male) C. Sagittal T2W MRI (female) D. Axial T2W MRI (female). Black arrows in all images show the anterior peritoneal reflection. U= uterus, R = rectum, P= prostate, SV=seminal vesicles. Anterior peritoneal reflection involvement (T4a) has to be confirmed on both axial and sagittal images.

35

Figure 4. White arrows in A (sagittal T2W MRI) and B (axial T2W MRI) show the dark rectovaginal septum which continues inferiorly into the perineal body. ** Shows the retrorectal space.

36

Figure 5. Levator and Sphincter complex A. Coronal T2W MRI. Levator ani (short white arrows) inserting into puborectalis (long white arrow); anorectal junction (horizontal line); anal canal (vertical line); internal sphincter (*), intersphincteric space (vertical long black arrow) and external sphincter (horizontal black arrows). B. Sagittal T2W MRI. Arrow shows posterior proximal attachment of levator ani to tip of coccyx.

37

Figure 6. Template for primary staging (structured report)

38

Figure 7. Mucinous tumor. A. Axial T2W MRI showing bright stromal signal of mucinous tumor (arrow) from 11’o’clock to 7’o’clock B. Axial T1W MRI showing dark signal of mucin (arrow) and C. ADC map. Arrow showing bright signal signifying absence of restriction (characteristic in mucinous tumors)

Figure 8. T3a and T3b tumors Axial T2W MRI, A. shows tumor (*) from 2’o’clock to 8’o’clock position with extramural spread <1mm at 4’o’clock (arrowhead) suggesting T3a category. Short white arrows show the uninvolved mesorectal fascia. B. Shows tumor (*) from 11’o’clock to 5’o clock position with extramural spread = 3mm at 2-3’o’clock (arrow) suggesting T3b category.

39

Figure 9. T3c and T3d tumors.Axial T2W MRI, A. shows intermediate signal intensity tumor with extramural spread (arrows) at 11 to 12 ‘o’clock, >5mm but < 15mm (T3c) B. Extramural spread (arrows) is seen at 4 to 6 ‘o’clock > 15mm in depth (T3d) and reaches the mesorectal fascia at 6’o’clock position.

40

Figure 10. Axial T2W MRI B=bladder, U=uterus. White arrow shows intact muscularis. Black arrows show invasion of muscularis and intermediate signal intensity broad pushing edge of tumor and spread into perirectal fat <1mm (T3a). Dashed black arrows at 3 and 4 ‘o’clock show low signal intensity thin spicules s/o desmoplastic reaction (fibrosis).

41

Figure 11.T4b tumors. A. Sagittal T2W MRI. Bulky rectal tumor (*) is seen invading the uterus (U) along the posterior wall (arrows). B. Axial T2W MRI shows a circumferential bulky rectal tumor (*) invading prostate (P) in the peripheral and central zones (arrows). Block arrow shows the lateral extension of tumor invading the left piriformis muscle (m).

42

Figure 12: T4a tumors, A. Sagittal T2W MRI in female & B. Axial T2W MRI in female show tumor (*) extending extramurally to invade anterior peritoneal reflection (black arrows), U= uterus. C. Sagittal T2W MRI in male & D. Axial T2W MRI in male show circumferential tumor (*) extending to invade the anterior peritoneal reflection (white arrows).

43

Figure 13. MRF Invaded. Axial T2 W MRI shows tumor (*) with extramural spread at 5’o’clock to 9’o’clock, reaching mesorectal fascia (MRF) at 6-7 ’o’clock (white arrow). Black arrows show regions of uninvolved MRF.

44

Figure 14. Coronal T2W MRI A. shows tumor (*) confined to rectum without invasion of the sphincter (ellipse), intersphincteric space (dashed arrow) or levator (solid arrow) B. Shows invasion of the intersphincteric space(dashed arrow). Tumor reaches up to the mid third anal canal (*).

45

Figure 15. Loco-regional nodes. A. Axial T2W MRI shows an enlarged rounded mucinous right lateral pelvic sidewall node (arrow). However mucinous nodes of any size are considered metastatic. B. Sagittal T2W MRI. Arrow shows enlarged presacral node that is also rounded and heterogeneous.

46

Figure 16.EMVI. Axial T2W MRI shows a circumferential rectal tumor (***) with extramural extension into a vessel at 2’o’clock which looks elongated and finger like (arrow). The vein is filled with intermediate signal intensity of tumor instead of the normal flow void, is expanded and shows fragmented margins.

47

Figure 17. Restaging MRI template (structured report)

48

Figure 18. Poor response at restaging. Sagittal T2W MRI. A. Primary staging MRI & B. Post neoadjuvant CRT Restaging MRI. There is no significant change in the size and morphology of the circumferential mucinous adenocarcinoma (arrows) after CRT. Mucinous and signet ring cell adenocarcinomas tend to respond poorly to CRT.

49

Figure 19. Regression in dimensions at restaging A. Pretreatment and B post neoadjuvant CRT sagittal T2W MRI showing significant regression in tumor bulk (asterisks). The distance of tumor from anal verge (double ended arrows) has increased and the tumor length (dashed arrow) has decreased.

50

Figure 20.Tumor & Node regression A. Pretreatment & B. Restaging axial T2W MRI show the tumor along left lateral wall in A (block arrows) has regressed in B (black arrows), thickness shown by dashed lines. There is decrease in tumor signal in B s/o fibrosis. The curly pointers shows the MRF invaded at 12’o’clock, which in B shows fibrosis and retraction. C & D. yN0 status Axial T2W MRI. The node in C (white arrow) has regressed significantly and is barely visible in D with fragmented margins. A size < 5mm is considered yN0. The other node in C (black arrow) has also regressed to <5mm and also shows low signal (fibrosis).

51

Figure 21. yMRF status. Axial T2W MR images A. Pretreatment and B. Post neo-adjuvant CRT, showing regression in tumor (* in A) to a low signal intensity fibrotic residue in B . Note change in MRF positive status at 12’o clock position (arrow in A) , to MRF negative status in B (arrow) due to clear perirectal fat plane between tumor and MRF C. Another case post neo-adjuvant CRT shows a fibrotic thickened mesorectal fascia (arrows)

Figure 22. A. Pretreatment axial T2W MRI shows semi circumferential tumor 3’o’clock to 9’o’clock (arrows) B. Post neoadjuvant restaging MRI shows tumor regression with bright signal (arrows) due to mucinous degeneration C. Restaging MRI often shows post CRT submucosal edema (black arrows). Residual tumor is seen at a higher level (white arrow).

52

Figure 23. mrTRG 1 (complete response) in two different patients. A & B. Axial T2W MRI C &D. Sagittal T2W MRI A. & C. Pretreatment status B & D. Post neoadjuvant Restaging MRI. Tumors seen in A (arrow) & C (*) have undergone complete response in B & D. A normal 3-layered rectum is seen in the first patient in B (arrow).

53

Figure 24. mr TRG2 (near complete response). Axial T2W MRI A. shows intermediate signal intensity circumferential tumor (*), which in B shows response to a low signal intensity completely fibrotic residue (arrows) suggestive of near complete response.

54

Figure 25. Impact of DWI. A.B & C. Pretreatment images (axial T2W MRI, DWI high b value image and ADC map) shows tumor from 8’o’clock to 2’o’clock, which has high signal on high b value image and low signal on ADC map (arrows).D. E. & F. Restaging post neoadjuvant CRT MRI ( axial T2W, DWI high b value image and ADC map). D. shows tumor regression with residual thickening from 9’o’clock to 2’o’clock- ? fibrosis ?tumor E & F High b value DWI & ADC maps show no restriction from 10’o’clock to 2’o’clock; appearing dark on both images (T2 dark through effect) , confirming fibrosis. A small focus of high signal (short arrow) on high b value image without corresponding low signal on ADC map is equivocal. The high signal seen posteriorly in the wall in E and F (long arrows) also show high signal on the T2W image and are probably due to submucosal edema.

55 Table 1. AJCC 8th edition staging for rectal cancer [7]

T category

T0

No e/o primary tumor

Tis

Carcinoma in situ; intraepithelial or invasion of lamina propria

T1

Tumor invades submucosa

T2

Tumor invades muscularis propria

T3

Tumor invades subserosa and perirectal tissues

a

< 1mm

b

1-5 mm

c

> 5mm-15mm

d

> 15mm

T4 a

Tumor penetrates to surface of visceral peritoneum

b

Tumor invades or is adherent to other adjacent organs or structures

56 N category

Nx

Regional nodes cannot be assessed

N0

No regional nodal metastasis

N1 a

1 lymph node

b

2-3 lymph nodes

c

Tumor deposits in subserosa, mesentery/ nonperitonealized perirectal tissues (may not be differentiated from nodes on imaging)

N2 a

4-6 nodes

b

7 or more regional nodes

M category

M0

No distant metastases

M1 a

Metastases in one organ

b

Metastases in more than one organ

c

Metastases to the peritoneum with/without other organ involvement

57

Table 2: Disease categories and MRI criteria* [6, 8-9] Disease

Stage descriptor

Risk of local recurrence

T1/T2, N0, M0

Low

category

Early

(Treated with surgery TEM/TME) UNITED STATES

Locally

(NCCN)

advanced

T3-T4, N1-N2

Moderate to high (Treated with neoadjuvant treatment followed by surgery if feasible)

Early

T1, T2, T3a and N0

Low

Intermediate T3b and higher, MRF clear, EMVI negative

Moderate

UK (NICE)

MRF invaded or levator Advanced

involved or low tumor invading intersphincteric plane

High

58

T1/T2 (for all cancers) T3a/b (for mid and upper rectal) Early

Low

AND No nodes EMVI negative MRF clear

Europe

T3a/b with MRF clear and

(ESMO)

levators free (for low rectal) Intermediate T3a/b, N1-N2, EMVI

Moderate

negative (for mid and upper rectal)

T3c/d with MRF clear and levators free (for low rectal) Locally advanced

High T3c/d, N1-N2, EMVI positive (for mid and upper rectal)

T3 with MRF invaded Advanced

T4b Lateral lymph nodes positive

High

59

TEM: Transanal endoscopic microsurgery; TME: total mesorectal excision; MRF: Mesorectal fascia, EMVI: Extramural vascular invasion (* From definitions specified in the guidelines of European Society Of Medical Oncology (ESMO), UK National Institute of Health & care Excellence (NICE) and US National Comprehensive Cancer Care (NCCN) network)

Table 3: Commonly performed surgeries performed in rectal cancer Type of surgery A. Transanal endoscopic

Structures removed

Indication

Focal endoscopic resection of

For T1 sm1 tumors

tumor

[< 30%

microsurgery (TEM)

circumferential, moderately or well differentiated, <3cm and located within 8cm of anal verge]

B. Total Mesorectal Excision (TME)

Defines the lateral extent of

A. Upfront:

surgery in rectal cancer.

For T1 ≥ sm2

Standard surgery for rectal

tumors;

cancer in which rectum and

T2 tumors

mesorectum is removed up to the

T3 a & b tumors

mesorectal fascia. Superiorly

(Europe)

dissection is up to the root of inferior mesenteric artery and

B. Post neoadjuvant

60 includes superior rectal and

CRT

inferior mesenteric nodes. Pelvic

T3 c & d, T4 tumors

sidewall nodes are not removed.

(Europe)

Defines the caudal extent of

For tumors reaching

TME surgery where the

above anorectal

resection

anastomosis is below the anterior

junction

(LAR)

peritoneal reflection but located

C. Low anterior

above the anorectal junction and the sphincter is entirely preserved

D. Intersphincteric resection (ISR)

Defines the caudal extent of

For tumors invading

TME surgery where distal

the IAS, but sparing

resection margin is below the

the intersphincteric

anorectal junction; the internal

plane and EAS. The

sphincter (IAS) is either

disease should not

completely removed (total-ISR)

caudally reach the

or partially removed (one third

distal third of IAS.

removal =partial-ISR and two thirds removal =subtotal-ISR). The dissection is within the intersphincteric plane; external anal sphincter (EAS) is entirely preserved to maintain continence. Defines the caudal extent of

For tumors reaching

61

E. Abdomino-perineal Excision (APE)

TME surgery where distal

below the anorectal

resection margin is below the

junction, laterally

anorectal junction; the entire

invading beyond IAS,

anal canal/sphincter complex is

but not threatening

removed and patient has

or involving the

permanent colostomy.

levator; or invading IAS alone up to the anal verge.

Defines the caudal extent of

For tumors reaching

TME surgery where distal

below the anorectal

resection margin is below the

junction invading

F. Extalevator

anorectal junction; a radical

entire transverse

abdomino-perineal

form of APR where the entire

thickness of sphincter

excision (ELAPE)

anal canal/ sphincter complex is

complex reaching

removed along with en bloc

beyond to threaten or

removal of the levator complex;

invade the levator

patient has permanent

ani.

colostomy. Removal of adjacent organs

When adjacent

along with APE/ELAPE

organs are involved

Dissection of the internal iliac

When pelvic sidewall

H. Lateral lymph node

and obturator (loco-regional)

nodes have not

dissection

nodes as well as external iliac

responded to

(non-loco-regional) nodes

radiation (nodes

G. Pelvic exenteration

(LLND)

≥5mm in size at

62 restaging) Table 4. MR Imaging recommendations [17-18,42] Essential

Hardware

Contraindicated Optional

External surface coil on a Endorectal coil 1.5T or 3.0T MRI system

Preparation

1) Bowels and bladder

Enema not

1)Spasmolytics

emptied

routinely

2)Endorectal

2) Supine and

needed

filling (not

comfortable on table

routinely advised with 71% against in the ESGAR 2016 guidelines)

Coil

1) Correct placement of

Placement

phased array coil (in low rectal cancers, distal edge of coil should be 10cm below the symphysis pubis) 2) Coverage should be for 5cm above the top of the tumor and at least up

63 to L5/S1 for all tumors

Sequences-

2 D T2-weighted FSE

Fat suppressed

*Large FOV non-

Primary

Orthogonal sequences

sequences

contrast T1-

staging

without fat saturation:

weighted Axial

a) Large FOV Axial &

Contrast

(for mucinous

Sagittal

enhanced T1-

deposits which

b) Small FOV Sagittal

weighted

have low contrast

c) Small FOV Coronal &

sequences

on T2-weighted

Axial (perpendicular and

sequences)

parallel to rectal tumor

Quantitative

axis) with slice thickness

ADC

3D T2-weighted

≤ 3mm

measurements

imaging

d) Low rectal cancers-

not routinely

small FOV coronal

advised

parallel to anal canal e) DWI with at least a

Routine DCE-

high b value ≥ 800

MRI

Sequences-

2 D T2-weighted FSE

Fat suppressed

*Large FOV non-

Restaging

Orthogonal sequences

sequences

contrast T1-

without fat saturation:

weighted Axial

a) Large FOV Axial &

Quantitative

(for mucinous

Sagittal

ADC

deposits which

b) Small FOV Sagittal

measurements

have low contrast

64 c) Small FOV Coronal &

not routinely

on T2-weighted

Axial (perpendicular and

advised

sequence)

axis) with slice thickness

Routine DCE-

Contrast

≤ 3mm

MRI

enhanced T1-

parallel to rectal tumor

d) Low rectal cancers-

weighted

small FOV coronal

sequences

parallel to anal canal e) DWI with at least a

3D T2-weighted

high b value ≥ 800

imaging

* - These sequences are included as essential in the authors’ practice

65 Table 5: MRI Protocol * Large FOV

Small FOV for Rectum

for Pelvis T2

DWI

T2 TSE

T2 TSE T2 TSE

T1 TSE

RESOLVE

TSE

Axial

Oblique

Sagittal

Coronal

Axial

DWI Axial

500-800

4500-6000

Axial TR (ms)

TE (ms)

Axial

4000-

8800-

4000-

3500-

3000-

5000

13000

6500

6000

5500

80-

75

85-100

85-100

85-100

12-24

55-60

14

13

4 -8

-

180 x

180 x

240x 240

190

180

180

100

ETL

5

-

13

FOV (mm

380 x

420 x

180x 180 190x

x mm)

330

315

Matrix

448 x

128 x

320 x

384 x

320 x

320 x

314

128

256

268

256

224

3

4

3

3

3

3

3

NA

0, 800

NA

NA

NA

NA

0, 800

Slice

110 x 110

thickness (mm) b values

* 3T, vendor Siemens

66 Table 6*: Criteria for N category [17]

Criteria for metastatic node at primary staging **-Morphological criteria: Maximum short axis ≥ 9mm 1. Round shape Maximum short axis 5-8 mm and with 2

2. Heterogeneous signal

morphological criteria**

3. Irregular margins

Maximum short axis < 5mm and with 3

-- Characterized on 2D T2-

morphological criteria **

weighted sequences and not DWI-MRI

Any size mucinous nodes

*Adapted from MRI for clinical management of rectal cancer: ESGAR 2016 consensus meeting [17].

67

Table 7: Performance of MRI at restaging [55] Sensitivity

Specificity

yT category

50.4%

91.2%

yN category

76.5%

59.8%

yMRF

76.3%

85.9%

68 Table 8: Tumor Regression Grade (TRG) on MRI* MRI appearance Grade mrTRG1 Complete response: No evidence of treated tumor

mrTRG2 Good response: Dense fibrosis without any obvious residual tumor

mrTRG3 Moderate response: > 50% fibrosis or mucin along with intermediate intensity tumor

mrTRG4 Slight response: Small areas of fibrosis/mucin with mostly tumor

mrTRG5 No response: No change in appearance or bulk from original tumor

*[Adapted from references 1,62]

69 Table 9: Changes/additions since 2018 in AJCC staging, ESGAR recommendations and other guidelines Parameter

Descriptor 

M category – M1a, M1b, M1c [7]

8th edition AJCC Staging



Involvement of mesorectal fascia (MRF) is T3 [17]

and additions to it



Involvement of internal anal sphincter is T3 [17]



Involvement of pelvic sidewall structures (muscles, vessels, nerves and bone) is T4 [4,17]

Hardware



Minimum magnet strength = 1.5 T [17]



Minimum slice thickness =3mm [17-18]



Diffusion weighted imaging (DWI) essential for both primary staging and restaging [17-18]



For DWI, a high b value of at least 800 mandated [17]



DWI evaluated with visual inspection of high b value

Sequences

image and ADC map; quantitative measurements not required [17] 

Add one of the following sequences for mucinous tumors: non-contrast T1-weighted sequence [18] preferred by authors or contrast enhanced T1-weighted or fat suppressed T2-weighted sequences [4]

70

Reporting



Structured reporting essential for staging and restaging [17]



Circumferential Tumor location in o’ clock to be mentioned in addition to distance from anal verge and anorectal junction [17]



Tumor morphology to be mentioned and especially whether mucinous or non mucinous



T3 subcategory (a/b/c/d) to be specified [17]



T4 subcategory (a/b) to be specified [17]



MRF— only distance of tumor to MRF to be considered to decide positive status (not node/ deposit/EMVI); however

Elements in reporting

node, deposit or EMVI close to MRF need mention to help plan CRM-negative surgery [4]. 

Low rectal cancer: T category not to be applied; instead mention separately involvement of internal sphincter, intersphincteric space, external sphincter and levator complex [4,17].



N category- new nodal criteria specified at primary staging (Table 6) for mesorectal nodes (can be used for pelvic sidewall nodes too). Another criterion for pelvic sidewall nodes by Ogura et al : >7mm at primary staging should be considered abnormal [50].

71 

yN category - At restaging all nodes ≥ 5mm considered yN+ [17,56]; nodes <5mm are yN0



EMVI: to be specified at both staging and restaging [17]



Response (yMRI) – At restaging, a measure of response to be mentioned in the report (Absent or Minimal response/ Partial response/Near-complete response/ Complete response) using mrTRG and DWI. Presence of suspected residual disease to be mentioned.