Fig. 27.1
Management algorithm for nonmetastatic primary rectal cancer (ESD endoscopic submucosal dissection)
The diagnostic accuracy of EUS in rectal cancer staging has recently been questioned and criticized as clinical practice and literature do not appear to support the early very positive reports. A German multicenter, prospective, quality assurance study evaluated 7000 patients between 2000 and 2008 and compared radial EUS findings to surgical pathology T stage without the use of neoadjuvant therapy [2]. While the T stage concordance was only 65 %, increasing procedure volumes improved their results. The frequency of under- and overstaging was 18 and 17 %, respectively. Another report from a US center conducted between 1993 and 2007 revealed that EUS nodal evaluation with imaging alone without FNA did not reliably identify patients with nodal disease. Their opinion was based on the finding of a 29 % false-positive rate and because 23 % of patients were understaged when compared to surgical pathology as the gold standard [3]. The conclusions of both reports have uncertain applicability to current practice, given that they evaluated radial EUS alone using technology dating back to the early 1990s. Current practice routinely incorporates linear imaging, FNA assessment of indeterminate nodes, and improved ultrasound technology.
The objective of this chapter was to provide a comprehensive overview using historical and current data to help understand the incremental benefit of EUS versus alternative imaging modalities for assessing patients with primary de novo rectal cancer, following neoadjuvant therapy and during postoperative disease surveillance utility. We also explore potential novel interventions.
Case Study
Initial Presentation
A 62-year-old male presented with a 2-week history of intermittent hematochezia. A digital rectal examination identified the distal border of a posterior lateral wall ulcerated mass. Endoscopic examination revealed a traversable 4-cm friable ulcerated polypoid mass with its distal border located at the distal valve of Houston, occupying 75 % of the luminal circumference. Mucosal biopsies confirmed the presence of adenocarcinoma. Abdominal CT revealed no evidence of metastatic disease. Pelvic MRI identified an enhancing 4-cm mass located approximately 7 cm from the anal verge with questionable extension through the muscularis propria and into the mesorectal fat. There was no involvement of the mesorectal fascia, with a 6 mm distance to the circumferential resection margin, and no evidence for invasion into adjacent structures. In addition, indeterminate 3- to 5-mm lymph nodes were found within the mesorectal fat. A rectal EUS examination was recommended.
What Are Useful Pearls for Initial Primary Rectal Cancer Assessment?
Anorectal Anatomy
The rectum extends from the upper end of the anal canal to the rectosigmoid junction and is approximately 12 cm in length [4]. It is subdivided into proximal, middle, and distal thirds. The surgically defined anal canal measures 2.5–4 cm in length with two-third above the dentate line and one-third below the dentate line [5]. The anatomic anal canal corresponds to the distal one-third of the surgical anal canal and spans from the dentate line to the anorectal verge. Above the dentate line, the anal canal is lined by columnar epithelium, whereas it is lined by squamous epithelium distal to the dentate line. The anal transitional zone corresponds to an approximately 10-mm-long segment between the columnar and squamous epithelial zones where the mucosa is of variable histology [6].
The rectal wall is composed of mucosa, submucosa, and muscularis propria. The mucosa comprises two wall layers: an outer hyperechoic layer (the interface between mucosa and the ultrasound probe) and an inner hypoechoic wall layer. The third wall layer is hyperechoic and represents the submucosa. The muscularis propria or fourth wall layer is composed of an outer longitudinal and inner circular smooth muscle layer. The inner circular smooth muscle becomes thickened distally and continues as the internal anal sphincter and the outer longitudinal muscle fuses with fibers from the levator ani [5]. The outermost layer of the sphincter complex is formed by striated muscles, the levator ani, and puborectalis muscles superiorly and by the inferior part of the external anal sphincter inferiorly.
The rectum is surrounded by mesorectal fat containing lymph nodes, superior hemorrhoidal vessels, and fibrous tissue collectively known as the mesorectum. The mesorectum is continuous with the fat of the sigmoid mesocolon superiorly and usually thicker along the posterior rectum in its intraperitoneal portion and on occasion is absent anteriorly. It is bound circumferentially by the mesorectal fascia. This fascia extends inferiorly and coalesces with Denonvilliers’ fascia in men anteriorly, and anterior to this fascia are the seminal vesicles and prostate gland. Conversely in women, the anterior mesorectal fascia coalesces with rectovaginal fascia, anterior to which is the vagina. The mesorectal fascia forms an important barrier to the radial spread of upper and middle third rectal tumors and forms the plane of dissection used in total mesorectal excision (TME).
Nodal drainage of the rectum occurs initially to the perirectal lymph nodes within the mesorectum [7]. The majority of nodes follow the rectal blood supply and are located superiorly and posteriorly. The common path of nodal spread is along the superior rectal artery into the apical mesorectum and the inferior mesenteric artery into the sigmoid mesocolon. The middle rectal artery arises from the internal iliac artery directly and the inferior rectal artery arises from the internal pudendal artery, a branch of the anterior division of the internal iliac artery. The inferior and middle rectal arteries anastomose at the anorectal junction and, although uncommon, distal rectal cancers can spread to the nodes along the internal pudendal and internal iliac arteries.
What Is the TNM Staging System for Rectal Cancer?
The tumor node metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) and the International Union against Cancer (UICC) has become the worldwide standard for staging colorectal cancer [8, 9]. The TNM system classifies the primary tumor (T) stage based on the depth of tumor invasion into and through the rectal wall. Nodal substations classified as regional lymph nodes for rectal cancer are perirectal, inferior mesenteric, sigmoid mesenteric, lateral sacral, presacral, sacral promontory, internal pudendal, internal iliac, superior rectal, middle rectal, and inferior rectal. Involvement of lymph nodes outside these groups, such as in the external or common iliac substations, is considered to be distant metastases (M stage) (Table 27.1).
Table 27.1
The 2010 American Joint Committee on Cancer (AJCC) staging system for primary rectal cancer
TNM | |
Tx | Primary tumor cannot be assessed |
T0 | No evidence of primary tumor |
Tis | Carcinoma in situ |
T1 | Tumor invades submucosa |
T2 | Tumor invades muscularis propria |
T3 | Tumor invades through the muscularis propria into pericolorectal tissues |
T4a | Tumor penetrates to the surface of the visceral peritoneum |
T4b | Tumor directly invades or is adherent to other organs or structures |
Nx | Regional lymph nodes cannot be assessed |
N0 | No regional nodal metastasis |
N1 | Metastasis in 1–3 regional lymph nodes |
N1a | Metastasis in one regional lymph node |
N1b | Metastasis in 2–3 regional lymph nodes |
N1c | Tumor deposit(s) in the subserosa, mesentery, or non peritonealized pericolic or perirectal tissues without regional nodal metastasis |
N2 | Metastasis in 4 or more regional lymph nodes |
N2a | Metastasis in 4–6 regional lymph nodes |
N2b | Metastasis in 7 or more regional lymph nodes |
Mx | Presence of distant metastasis cannot be assessed |
M0 | No distant metastasis |
M1 | Distant metastasis |
M1a | Metastasis confined to one organ or site (i.e., liver, lung, ovary, nonregional node) |
M1b | Metastases in more than one organ/site or the peritoneum |
EUS Technique
The examination is performed following a full colonoscopy preparation or 2 Fleets enemas and flexible sigmoidoscopy with a patient lying in the left lateral decubitus position to facilitate optimal visualization. The necessary features to document for endoscopic evaluation are highlighted in Fig. 27.2. The middle valve of Houston is thought to be a surrogate marker for the anterior peritoneal reflection, and the location of a tumor, if proximal or distal to the anterior peritoneal reflection, has important surgical planning implications.
Fig. 27.2
Endoscopic and EUS features to be evaluated during the examination
Following advancement of the echoendoscope to the sigmoid colon, air or CO2 is aspirated as the echoendoscope is withdrawn in order to improve acoustic coupling. The use of either a radial or a linear echoendoscope is a personal preference. Starting with a radial echoendoscope is very reasonable to readily visualize the rectal wall layers and assess for lymph nodes. In addition to aspirating air, water will likely be needed to fill the rectum to enhance imaging. The patient can be rotated to shift the water and allow it to submerge the mass. Care must be taken to establish the relationship of the distal tumor border to the seminal vesicles in men and the cervix in females. The presence or absence of adjacent organ involvement to include the prostate, bladder, and seminal vesicles in men, and the bladder, vagina, and cervix in women should also be noted. In addition, the perirectal and perisigmoid space should be evaluated for the presence of lymph nodes or omental lesions, irrespective of whether a radial or a linear echoendoscope is used. The advantage of beginning with the linear echoendoscope is the ability to image and FNA using the same instrument.
Endosonographically, the rectal wall is seen as five alternating hyper- and hypoechoic layers. A tumor that extends no deeper than the mucosa or submucosa is classified as a T1 lesion (Video 27.1). If the lesion enters the muscularis propria (hypoechoic fourth layer) but does not breach through, it is a T2 lesion (Fig. 27.3). Deeper penetration through the muscularis propria layer, extending beyond the rectal wall and into the surrounding perirectal fat, is consistent with a T3 lesion (Fig. 27.4). Finally, a T4 lesion implies direct invasion into an adjacent organ, i.e., the prostate gland, vagina, and bladder (Fig. 27.5).
Fig. 27.3
Comparative images of the rectal wall reflecting the mural changes between T1, T2, and T3 lesions
Fig. 27.4
An ulcerated friable mid-rectal T3 cancer penetrating through the muscularis propria layer, extending beyond the rectal wall and into the surrounding perirectal fat
Fig. 27.5
A radial EUS examination revealing infiltration anteriorly into the vaginal wall establishing a T4 lesion
EUS evaluation of this 4-cm distal rectal cancer revealed hypoechoic wall thickening to 11 mm with pseudopodia formation and 2-mm infiltration beyond the muscularis propria.
What Are the T Staging Pitfalls?
In published studies, the accuracy of EUS T stage ranges from 80 to 95 % compared with 65–75 % for CT and 75–85 % for MRI [10–12] . With respect to T stage, one particular problem for EUS is the overstaging of T2 tumors due to the difficulty in differentiating peritumoral inflammation and/or fibrosis from the cancer itself (Fig. 27.6) [13]. This tumor meets criteria for a T3 tumor because it did extend through the entire thickness of the muscularis propria into the perirectal fat and obliterated the well-defined fat–muscle interface by neoplastic pseudopodia. Accuracy of specifically T2 staging was examined in a retrospective study because this represents one major decision point in management of rectal cancers with higher T stage tumors receiving neoadjuvant therapy [14]. Both overstaging and understaging of actual T1 or T3 tumors occurred in 16 % to yield a negative predictive value for identifying tumor depth of T2 or less of 84 % and absence of nodal disease of 87 %. Incorrect EUS staging impacted management in 23 % of patients.
Fig. 27.6
a Postpolypectomy for malignancy with superficial ulceration secondary to cautery effect. b There is discrete mural hypoechoic change on EUS which cannot distinguish malignant from inflammatory change unless sampled by FNA
It is thought that all T3 rectal tumors are not clinically equivalent, with minimally invasive disease carrying a more favorable prognosis [15]. Therefore, by discriminating minimally invasive from advanced T3 disease (invasion ≤ 2 mm or > 3 mm beyond the muscularis propria), preoperative EUS may provide important prognostic information. However, the challenge is that overstaging is noted more commonly in minimally invasive T3 (50 %) when compared to advanced T3 disease [16]. The maximum tumor thickness of T3 cancers is also an independent prognostic factor for local and overall recurrence [17] using a cutoff value of ≥ 19 mm.
Understaging, conversely, may result from a failure to detect microscopic cancer infiltration owing to the limits of EUS resolution. Spatial resolution is improved by increasing ultrasound frequency, but at the expense of reduced depth of penetration that may compromise inspection of deeper structures. Other variables that influence the accuracy of tumor staging include operator experience and the location of the tumor within the rectum, with reduced accuracy for more distal tumors [13, 18–20]. A meta-analysis of 42 studies ( n = 5039; 1980–2008) reviewed the published data for EUS accuracy by the T stages, suggesting that EUS sensitivity is greatest for advanced disease (T3 or T4) rather than for early (T1 or T2) disease (Table 27.2) [21].
Table 27.2
EUS imaging T stage data
T stage | Sensitivity (%) | Specificity (%) |
|---|---|---|
T1 | 88 | 98 |
T2 | 80 | 96 |
T3 | 96 | 91 |
T4 | 95 | 98 |
EUS revealed a superficial T3 lesion, 3 round hypoechoic peritumoral lymph nodes as well as a 9 × 7 mm left common iliac artery lymph node. FNA of this node was performed.
What Are the Nodal (N) Staging Pitfalls?
EUS features that accurately predict nodal metastasis have been identified in patients with esophageal cancer [22]. These conventional echo features that correlate with malignancy include an enlarged node (≥ 1 cm in short axis), hypoechoic appearance, round shape, and smooth border (Table 27.3). For patients with esophageal cancer, if all four abnormal morphological features are present, the accuracy for malignant invasion is 80 %. However, all four features of malignant involvement are present in only 25 % of malignant lymph nodes (Fig. 27.7). Unfortunately, the standard conventional EUS nodal criteria have proven inaccurate for staging many nonesophageal cancers [22–24]. No one criterion is predictive of malignancy in patients with lung, esophageal, and pancreatic cancer.
Fig. 27.7
a, b A bulky T2N1 tumor with c nonperitumoral lymph nodes confirmed d malignant by FNA
Table 27.3
EUS morphological features of benign and malignant lymph nodes
EUS features | Benign LN features | Malignant LN features |
|---|---|---|
Echogenicity | Hyperechoic | Hypoechoic |
Shape | Irregular | Round |
Border | Irregular | Smooth |
Size (short axis) | < 10 mm | ≥ 10 mm |
The N stage accuracy for EUS imaging in the setting of any malignancy is only 70–75 % and was recently reported to be as low as 42 % [25, 26]. It was previously assumed that EUS was incapable, or only seldom able, to detect benign perirectal lymph nodes. Therefore, in patients with rectal cancer, mere visualization of lymph nodes was deemed an accurate surrogate marker of nodal metastasis, thereby obviating the need for FNA. A meta-analysis [35 studies ( n = 2732; 1966–2008)] of the EUS N stage accuracy in rectal cancer found that the sensitivity and specificity of EUS are moderate (approximately 75 %) and concluded that further refinement in diagnostic criteria is needed to improve the diagnostic accuracy [27]. An important limitation of their analysis was the dependence on mostly studies that imaged using radial instruments alone without FNA.
Prior transrectal ultrasound studies identified a nodal size of ≥ 7 mm as an optimal size cutoff for predicting nodal metastases in rectal cancer, with an accuracy of 83 % when compared with surgical pathology [28]. A dedicated FNA study, based on a perception that metastatic loco-regional nodes only minimally differ in morphological appearance from benign nodes, noted that the number of conventional malignant echo features present per lymph node did not accurately differentiate benign from malignant nodes, unless all four features were present (Table 27.4) [29]. The accuracy for each of the four conventional criteria (short axis ≥ 10 mm, hypoechoic appearance, round shape, and smooth border) for detecting malignancy is as follows: 61, 65, 51, and 51 %, respectively. A lymph node short-axis length ≥5 mm or a hypoechoic appearance was the only EUS feature predictive of malignant infiltration. Optimum short- and long-axis lengths of 6 and 9 mm, respectively, yielded the best power distinction for malignancy (Fig. 27.8).
Fig. 27.8
A distal T3N1 lesion in a 54-year-old male who proceeded to neoadjuvant therapy followed by surgery. The highlighted node is perilesional and therefore not amenable to FNA. It has a hypoechoic appearance and short axis > 5mm but oval in shape with an irregular border
Table 27.4
Performance characteristics relative to the number of malignant EUS nodal features
≥ 2 features | ≥ 3 features | 4 features | |
|---|---|---|---|
Sensitivity % | 77 | 68 | 23 |
Specificity % | 29 | 52 | 100 |
PPV % | 53 | 60 | 100 |
NPV % | 55 | 61 | 55 |
Accuracy % | 54 | 61 | 61 |
Using surgical histopathology specimens, Knight and colleagues assessed the performance characteristics of EUS-FNA in the setting of primary or metastatic colorectal carcinoma of perirectal masses, lymph nodes, and distant metastases. The overall sensitivity, specificity, and positive and negative predictive values were reported as 89, 79, 89 and 79 %, respectively [30].
The preoperative EUS-FNA identification of extramesenteric lymph node metastases upstages 7 % of primary rectal cancers. This is important because, for example, external iliac artery lymph node infiltration is outside the standard operative field for total mesorectal excision (TME). Nodal metastasis to this site typically impacts medical and surgical planning by extending the radiation fields and may indicate the need to extend the TME resection to include an extensive lymph node dissection [31]. Other markers that are associated with such metastases include serum CEA level, tumor length ≥ 4 cm, tumor annularity ≥ 50 %, sessile morphology, and lymph node size. Unfortunately, these potential surrogate markers are insufficiently accurate, and EUS-FNA is necessary to identify metastasis to these nodal stations.
These findings clearly indicate the need for EUS-FNA to verify nodal status, rather than relying on nodal morphology alone, when making critical decisions regarding the use of neoadjuvant therapy. Failure to do so risks stage inappropriate therapy and in turn inappropriate patient outcomes. We now favor routine FNA because (1) improved technology allows visualization of benign lymph nodes in virtually all patients, (2) most malignant nodes in the setting of rectal cancer are less than 1 cm in size, and (3) the predictive value of imaging alone for distinguishing benign from malignant nodes remains poor.
A note of caution is that luminal fluid cytology may be positive for malignancy in 48 % of luminal cancers, including rectal cancer, but is not affected by performing FNA [32]. These translocated cells may contaminate the FNA specimen and lead to false-positive FNA results. In addition, endosonographer technique and cytological misinterpretation also contribute to false-positive EUS-FNA cytology [33].
EUS-FNA of solid lesions in the lower GI tract is considered a low-risk procedure for infectious complications and does not warrant prophylactic administration of antibiotics for the prevention of bacterial endocarditis [34]. Perirectal cystic structures are considered a relative contraindication to FNA given the risk of abscess formation requiring percutaneous drainage, which has occurred despite the administration of prophylactic antibiotics [35]. If FNA is contemplated, we encourage discussion of the need and potential risks with the patients’ medical and surgical staff. A recent large single-center study of 502 patients undergoing EUS-FNA of lower GI lesions, over 80 % of which were for rectal cancer, highlighted that risk factors for adverse events included preprocedural pain, FNA of a site other than a lymph node or gut wall, and malignant cytology [36].
Case Follow-Up
The final interpretation of EUS was a superficial T3 tumor with indeterminate peritumoral nodes, but a malignant left common iliac artery lymph node, thus establishing a distal T3N1M1a rectal cancer. The patient proceeded to neoadjuvant therapy including expansion of the pelvic radiation fields. An abdominoperineal resection with an extended lymphadenectomy was subsequently performed.
Utility of EUS Compared to Other Staging Modalities
MRI Versus EUS Assessment
The role of MRI using an endorectal coil has been well established for local staging of rectal cancer [37–39]. It offers several theoretical advantages over EUS as it reveals a larger field of view and permits the study of stenotic, nontraversable tumors [18, 40, 41]. Recently, the identification of the anterior peritoneal reflection on MRI in 74 % of patients in one study is important given the impact of this landmark on surgical planning [42]. A meta-analysis of 90 articles (1995–2002) compared the utility of MRI, radial EUS without FNA, and CT for staging with histopathology correlation as the gold standard and came to the following conclusions: For T1/T2 lesions, EUS and MRI had similar sensitivity, but specificity was higher in EUS (86 vs. 69 %); for T3 tumors, the sensitivity of EUS was significantly higher than that of MRI or CT [43]. A more recent prospective study comparing radial EUS to MRI revealed that MRI was unable to visualize any T1 tumor , whereas EUS understaged all T4 tumors [44]. Furthermore, the presence of luminal stenosis and polypoid morphology was inversely associated with accuracy for either EUS or MRI.
MRI may also be used to evaluate mesorectal nodal involvement as lymph nodes may be assessed using size criteria as well as specific nodal imaging. The most reliable MRI criteria for lymph node metastasis when correlated with histological findings are an irregular contour and inhomogeneous signal [45, 46]. Many studies have evaluated the performance of MRI for assessing lymph node involvement. A meta-analysis from 2004 revealed that the sensitivity and specificity of MRI were 66 and 76 %, respectively, compared with 67 and 78 % for radial EUS without FNA and 55 and 74 % for CT [39, 43]. In another meta-analysis, there was similarly no significant difference in N staging between MRI and EUS, although EUS had a slight advantage in diagnostic specificity [47].
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