29 The Preoperative Staging of Rectal Cancer

29

The Preoperative Staging of Rectal Cancer

Jonathan E. Efron and Juan J. Nogueras

405 The classification of cancers of the rectum into a staging sys-

tem with both therapeutic and prognostic applications has been the goal of pathologists and clinicians for the greater part of the last century. Different staging systems for colorec- tal cancer are in use today; however, the majority are modifi- cations of a common framework using similar nomenclature with the unfortunate results of inconsistencies and confusion.

Most staging systems rely on examination of the pathologic specimen as well as information gained during surgery. Thus, they are useful only in the postoperative setting and have lit- tle use for the purpose of preoperative therapy. Cuthbert Dukes

declared in 1932 “if it would be possible to decide the category of the case before operating, this would be very use- ful information.” As the therapeutic options available for the treatment of rectal cancer increase, the ability to accurately stage a rectal tumor preoperatively takes on greater impor- tance. Accurate and reproducible preoperative staging pro- vides uniformity among numerous investigative centers;

specifically those involved in adjuvant preoperative therapy trials. Finally, the ability to stage the tumor preoperatively permits the physician to convey more accurate information to the patient and the family with regard to therapeutic options and prognosis.

The tumor-related factors of prognostic significance that are most useful in the preoperative staging of rectal cancers include the depth of penetration of the tumor through the rec- tal wall, the presence or absence of metastasis to the regional lymph nodes, and the presence of distant metastases.

Clinicians have a variety of diagnostic tools at their disposal that can aid in delineating these aforementioned factors. The most frequently used modalities for the preoperative staging of rectal tumors available today are clinical examination, computed tomography (CT), magnetic resonance imaging (MRI), endorectal ultrasonography (ERUS), and positron emission tomography (PET).

At the time of history and physical examination, other ini- tial evaluations are ordered. Laboratory tests including CEA

(carcinoembryonic antigen) levels and liver function tests may also provide useful information in patients with rectal cancer. There is a small risk of metastatic spread of rectal can- cer to the lung, bypassing the liver, therefore a baseline chest X-ray should also be obtained.

Clinical Evaluation

Because of its anatomic location, clinical examination of the rectum can be performed with minimal discomfort to the patient. Careful digital assessment of the rectal tumor may yield valuable information. Table 29-1 lists some of the important parameters that should be recorded during the physical examination of a rectal tumor. A clinical staging system based on tumor mobility was first established by York-Mason

in 1976 and subsequently modified in 1982.

In this clinical staging system, tumor mobility is correlated with the level of tumor penetration in the different layers of the rectal wall (Table 29-2). Nicholls et al.

evaluated this clini- cal staging system and discovered that senior examiners had an 80% accuracy in distinguishing CS1 and CS2 tumors from CS3 and CS4 tumors, but only a 50% accuracy in detecting lymph node metastasis. The accuracy was directly propor- tional to the experience of the examiner. Factors that facili- tated clinical assessment were the number of quadrants involved, the mobility of the tumor, and palpable extrarectal growths. This study clearly showed that useful information can be obtained from digital examination of rectal tumors.

However, certain limitations of a digital examination must be recognized. The accurate assessment of early invasion into the rectal wall has been disappointing, especially in selecting patients for local excision of such a tumor. Clinical staging is more accurate in correctly assessing the stage of more advanced lesions where local excision is not an option.

Finally, only tumors of the mid and distal rectum can be

assessed by digital examination.

Local and Regional Staging

CT Scan

CT scan is helpful in providing an image of the entire pelvis and the relationship of the tumor to surrounding pelvic struc- tures especially for advanced tumors. However, CT scan has not proven to be very accurate in determining the depth of penetration of the tumor through rectal wall or assessing involved perirectal lymph node metastasis.

Table 29-3 summarizes the results of several studies in which CT scan was used to delineate the penetration of the tumor through the rectal wall and the presence or absence of involved perirectal lymphadenopathy.

The reported accuracy rate of CT scan in determining tumor penetration through the rectal wall ranges from 52% to 100%.

CT scan is unable to depict the layers of the rectal wall. Thus, for tumors that are confined to the rectal wall, CT scan cannot distinguish tumors that are confined to the submucosa from those that have breached the submucosa and involve the mus- cularis propria. In cases of advanced tumor growth, CT scan

does provides valuable information about the relationship of the tumor to the surrounding viscera and pelvic structures.

The accuracy of CT scan in determining lymph node involvement ranges from 35% to 70%. One drawback of CT scan is its inability to detect lymph nodes smaller than its resolution threshold of 1 cm. A second drawback of CT scan for the assessment of perirectal lymph node metastasis is its inability to differentiate between tumor metastasis and inflammation in enlarged lymph nodes.

New technology such as the multidetector-row CT (MDRCT) may significantly improve the ability of CT scans to accurately determine the depth of invasion and lymph node metastasis in rectal cancer. MDRCT utilizes four detectors which result in a much higher resolution and better multipla- nar reformation of the images. Matsuoka et al.

compared 21 patients who had MDRCT with 21 patients that had MRI evaluations of the pelvis for rectal cancer. They reported an accuracy rate of 95% on depth of invasion for MDRCT ver- sus 100% for MRI, whereas lymph node accuracy was 70%

versus 61% for MDRCT and MRI, respectively.

Magnetic Resonance Imaging

MRI is a relatively new modality for the staging of rectal can- cer. Since its original description in 1986,

multiple studies have compared the accuracy of MRI in staging rectal cancers with other imaging modalities such as CT scan and ERUS.

Accuracy rates for MRI in the preoperative staging of rectal cancer have varied according to technique.

The traditional body coil MRI studies have ranged in accu- racy from 55% to 95%.

The addition of an endorectal coil to this technique resulted in T stage accuracy rates of 66%–91%.

These results are listed in Table 29-4.

Kim et al.,

in the largest published trial to date examining the accuracy of MRI staging of rectal cancer, compared the histopathologic staging with the preoperative staging in 217 patients. The accuracy for the depth of invasion was 81% and for regional lymph node metastasis was 63%. Their technique involved injection of intravenous contrast material and exam- ining T1-weighted spin-echo images and T2-weighted turbo spin-echo images. Brown et al.

examined preoperative prog- nostic factors in 98 patients with rectal cancer using high-res- olution MRI with a thin section technique. A whole body scan was performed and only T2 weighted images were examined.

The accuracy rate in assessing the T stage was 94%, for lymph node involvement was 84%. In their article, Brown et al.

introduced new criteria to define MRI T staging (Table 29-5). MRI identification of metastatic lymph node involve- ment has not been standardized, which may explain the great variation in accuracy. Kim et al.

considered lymph node involvement if they demonstrated heterogeneous texture, irregular margins, or were enlarged to greater than 10 mm.

However, Brown et al.

demonstrated that lymph node size was not an accurate predictor of metastatic disease and, there- fore, they relied on mixed signal intensity and irregular or T

29-3. Accuracy of CT scan in preoperative staging of rectal

cancer

No. of T staging N staging

patients (%) (%)

Dixon et al., 1981

47 78 49

Grabbe et al., 1983

54 79 56

Freeny et al., 1986

80 62 35

Thompson et al., 1986

25 70 35

Holdsworth et al., 1988

17 94 70

Goldman et al., 1991

30 52 64

Zerhouni et al., 1996

365 74 62

Matsuoka et al., 2002

20 100 70

Chiesura-Corona et al., 2001

105 82 79

Harewood et al., 2002

80 71 76

T

29-2. Clinical staging system

Pathologic correlation Clinical stage Mobility (level of invasion)

CS1 Freely mobile Submucosa

CS2 Mobile with rectal wall Muscularis propria CS3 Tethered mobility Perirectal fat CS4 Fixed/tethered fixation Adjacent tissues T

29-1. Tumor characteristics to assess on digital examination Location

Morphology

Number of quadrants involved Degree of fixation

Mobility

Extrarectal growths

Direct continuity

Separate

ill-defined borders of the lymph nodes. Further studies need to be performed to determine the accurate predictors of lymph node metastasis on MRI.

In recent years, tumor involvement of the circumferential resection margin (CRM) has been identified as an important predictor of locoregional recurrence in rectal cancer patients undergoing a radical proctectomy with total mesorectal exci- sion (TME).

Postoperative radiation is not effective in reducing the risk of local recurrence in patients with a positive CRM,

and a curative operation in these patients will require either tumor downstaging by preoperative chemoradion, an extended resection, or both. Consequently, the preoperative assessment of the relationship of the tumor with the fascia pro- pria of the rectum, the CRM in patients treated with TME, has become of utmost importance in deciding the type of neoadju- vant therapy and planning the surgical resection. The fascia propria of the rectum is well visualized by phased-array coil or endorectal coil MRI and several studies have suggested that MRI can predict with high degree of accuracy the distance of the tumor to the fascia propria of the rectum.

Furthermore, because of its multiplanar capabilities, MRI is the most accu- rate imaging technique in assessing the relationship of the tumor with the levator plate and the sphincter complex. This information may be useful in selecting patients with low rectal

cancer for a sphincter-saving procedure. Therefore, MRI with a surface coil provides useful information in patients with locally advanced rectal cancer.

Endorectal Ultrasound

Recently, there has been much interest in the technique of ERUS for the preoperative staging of rectal tumors. This approach is proving to be safe, reliable, and relatively inex- pensive. It is an outpatient procedure requiring only enema preparation and no sedation or anesthesia. The frequency of the ultrasound transducer determines its focal range and ultra- sonographic resolution. Complete circular imaging of the rec- tal wall can be obtained with the 360-degree rotating endorectal probe. Most investigators are now using a 7.0- or a 10-mHz transducer which provides a five-layer anatomic model of the rectal wall with three hyperechoic circles and two hypoechoic concentric circles (see Chapter 7).

Hildebrandt and Feifel

proposed a preoperative staging classification based on the ultrasonographically determined depth of pene- tration to the TMN classification system (see Chapter 7).

Table 29-6 lists the results of ERUS in the preoperative staging of rectal cancer.

The accuracy of the ultra- sound in determining the depth of penetration of the tumor through the layers of the rectal wall varied from 60% to 93%.

As with all modalities, there is a significant learning curve associated with the interpretation of the ERUS image. Orrom et al.

at the University of Minnesota demonstrated an accu- racy of 75% in the overall group; however, when they looked at their last 6 months of the study, the authors showed an improvement with a 95% accuracy in determining depth of invasion. Overall, 5% of the tumors were overstaged. This tendency to overstage tumors was a common finding through- out this series because of the inability to differentiate perirec- tal inflammation from tumor infiltration in the perirectal fat.

Orrom et al. also point out some of the pitfalls in performing this examination.

These authors routinely use a proctoscope to introduce the ultrasound probe, thereby ensuring that a T

29-4. Accuracy of MRI in the preoperative staging of rectal cancer

Year No. of patients T staging (%) N staging (%)

de Lange et al.

1990 29 89 65

Chan et al.

1991 12 91 75

Okizuka et al.

1993 33 88 88

Thaler et al.

1994 34 82 60

Schnall et al.

1994 36 81 72

Joosten et al.

1995 15 66

Indinnimeo et al.

1996 23 78 79

Hadfield et al.

1997 38 55 76

Zagoria et al.

1995 10 80

Kim et al.

2000 217 81 63

Gagliardi et al.

2002 28 86 69

Brown et al.

2003 94 85 84

Low et al.

2003 48 85 68

*

Endorectal coil used in MRI.

T

29-5. MRI T staging as proposed by Brown et al.

MRI T stage

T1: Low signal in the submucosal layer or replacement of the submucosal layer by abnormal signal not extending into circular muscle layer.

T2: Intermediate signal intensity within muscularis propria. Outer muscle coat replaced by tumor of intermediate signal intensity that does not extend beyond the outer rectal muscle into perirectal fat.

T3: Broad-based bulge or nodular projection (not fine speculation) of inter- mediate signal intensity projecting beyond outer muscle coat.

T4: Extension of abnormal signal into adjacent organ; extension of tumor sig- nal through the peritoneal reflection.

Source: Brown et al.

Copyright British Journal of Surgery Society Ltd.

Reproduced with permission from John Wiley & Sons Ltd. on behalf of the

BJSS Ltd.

complete image of the tumor is obtained. This eliminates the possibility of error in the situation whereby a tumor is less invasive distally and more invasive proximally. A blind inser- tion of the endorectal probe has the potential to inadequately visualize the entire tumor and miss a proximal level of deeper invasion.

A longer-term follow-up of the Minnesota series was pub- lished in 2002 by Garcia-Aguilar et al.

These investigators reported their experience with 1184 patients with rectal carci- noma or villous adenoma that underwent endorectal ultra- sonography. Histopathologic correlation was available for the 545 patients who had no prior radiotherapy. The accuracy of ERUS in assessing level of penetration was 69%, with 18%

overstaged and 13% understaged. The accuracy for nodal involvement in the 238 patients who had radical surgery was 64% with 25% overstaged and 11% understaged. The overall accuracy in this large series is lower than previously reported.

However, in this series, patients with locally advanced tumors that received preoperative radiation were eliminated from the analysis. The accuracy was higher for benign lesions, and for full-thickness lesions. Lower accuracy rates occurred for T1 and T2 lesions.

Preoperative radiation of rectal cancer causes various degrees of tumor regression resulting in scarring and fibrosis that impairs ultrasound imaging interpretation. Napoleon et al.

examined the results in determining depth of wall inva- sion in patients who had received radiotherapy and compared them with a group of patients with no previous radiotherapy.

These authors determined that depth of wall invasion was cor- rectly determined in 86% of patients without radiotherapy, but in only 47% of those patients in whom previous radiotherapy had been administered. Therefore, endorectal ultrasonogra- phy should be performed in the patient before receiving radio- therapy in order to increase its accuracy rate.

The accuracy in determining lymph node involvement with the ERUS varies from 68% to 83% (Table 29-6).

Normal mesorectal nodes are not visualized with ERUS;

visible nodes are considered pathologic. However, ERUS cannot differentiate between inflammatory or neoplastic nodes. Hildebrandt et al.

have described different echogenic parameters in nodes that were replaced by tumor as com- pared with inflammatory lymph nodes. They determined that hypoechoic lymph nodes represented tumor metastases whereas hyperechoic lymph nodes represented inflammatory changes. They reported an overall accuracy rate of 78% and they attributed their errors to micrometastases, mixed lymph nodes, and changing echo patterns within inflammatory nodes.

Andersson and Aus

reported a case in which a transrectal ultrasound–guided biopsy of a hypoechoic perirectal lymph node was performed in order to verify metastatic growth in a patient who had already undergone a local excision of a rec- tal cancer. Harewood et al.

investigated the impact of ERUS- guided fine-needle aspiration of perirectal nodes in the preoperative staging of 80 consecutive patients with rectal cancer. In this series, fine-needle aspiration did not signifi- cantly improve nodal staging over ERUS.

Based on these results, and the potential risk of spreading cancer cells into the mesorectum in patients with metastatic lymph nodes, ultra- sound-guided biopsy of enlarged perirectal nodes is not rou- tinely used in clinical practice.

Several prospective studies have compared ERUS and MRI in the preoperative staging of rectal cancer. Surface coil MRI is less accurate than ERUS in assessing rectal wall invasion and is primarily used for the staging of locally advanced rec- tal cancers. MRI with endorectal coil allows visualization of the different layers of the rectal wall, and can potentially be used for the preoperative staging of early rectal cancers.

Kwok et al.

performed a systematic review of the literature to compare the accuracy of several imaging techniques in the preoperative staging of rectal cancer. They concluded that ERUS has the highest sensitivity and specificity in assessing wall penetration, but MRI with endorectal coil had higher accuracy than ERUS in assessing nodal metastasis. However, MRI with endorectal coil is cumbersome to the patient, tech- nically difficult, and not widely available.

Three-dimensional ultrasound is a new technique that has recently been developed. Kim et al.

compared the accuracy of conventional ultrasound to three-dimensional ultrasound in the staging of rectal cancer. They found no significant differ- ence in accuracy of either depth of invasion or lymph node metastasis. Their study was small and there was a trend to higher accuracy with the three-dimensional ultrasound.

Further investigation is required for the evaluation of three- dimensional ultrasound on rectal cancer staging.

Distant Metastases

The detection of distant metastasis is of prime impor- tance for the accurate staging of rectal cancer. The most common site of distant spread of rectal cancer is the liver.

T

29-6. Accuracy of ERUS in preoperative staging of rectal cancer

No. of T staging N staging

patients (%) (%)

Hildebrandt and Feifel, 1990

137 88 73

Beynon et al., 1989

100 93 83

Jochem et al., 1990

50 80 72

Milson et al., 1990

52 83 70

Orrom et al., 1990

77 75 82

Goldman et al., 1991

32 81 68

Thaler et al., 1994

37 88 80

Starck et al., 1995

34 88 71

Nielsen et al., 1996

100 85 66

Massari et al., 1998

75 91 76

Harewood et al., 2002

80 91 82

Garcia-Aguilar et al., 2002

545 69 64

Marusch et al., 2002

422 63 —

Hull et al., 2004

411 60 —

The most frequently used imaging modalities used today to detect liver metastasis are abdominal ultrasound and CT scans. MRI and intraoperative ultrasound are now used with increasing frequency, particularly in patients with known metastasis that are considered candidates for surgical resection.

Studies that have investigated the use of preoperative ultra- sonography and CT in the detection of liver metastases have reported an overall accuracy ranging from 66% to 90%.

Table 29-7 lists some of the results of these earlier studies.

Clarke et al.

investigated the accuracy on intraoperative ultrasonography in detecting liver metastasis according to their location by anatomic liver segments. Both techniques were similar in detecting liver metastasis except for lesions located in the lateral segment of the left lobe of the liver where preoperative ultrasonography was accurate (76%) com- pared with CT scan (29%). The lower resolution of CT scan in the left lateral segment lesions was attributed to artifacts from the stomach and cardiac motion.

Ward et al.

from the National Institute of Health reported the results of a study evaluating preoperative CT with various enhancement techniques and MRI of the liver. All patients eventually underwent laparotomy with intraoperative ultra- sonography in some cases. Correlation of the imaging tech- niques with surgical findings was performed to determine the specificity and sensitivity of each test. The authors concluded that the MRI examination had the lowest false-positive rate and proved to be the best hepatic imaging study in the detec- tion of colorectal metastases.

Despite refinements in enhancement techniques of CT

and external ultrasounds, along with the addition of MRI, the resolution threshold for liver metastases remains at approxi- mately 1 cm. For lesions in the left lateral segment of the liver, this threshold is larger. Even after preoperative imaging, up to one-third of colorectal cancer patients are found at the time of surgery to have unsuspected additional liver lesions or extra- hepatic metastases. Other modalities used to detect metastatic disease not seen with conventional imaging techniques are PET scan and radioimmunoscintigraphy.

PET scans have been shown to have higher sensitivity and specificity in detecting recurrent rectal cancer than both CT and MRI.

Although sensitivity and specificity in diagnos- ing tumor recurrence are higher for PET scans, its spacial resolution is not very accurate and therefore other studies such as MRI and/or CT scans are required to define the

precise location of the tumor to important anatomic landmarks. Current scanners are available that fuse CT or MR images with the PET scan images. The ability of these fused images to increase sensitivity or specificity is being investi- gated. Cohade et al.

compared PET scan and PET/CT images in a series of 45 patients with colorectal cancer. They found that the overall staging accuracy increased from 78% to 89% with PET/CT. PET scans when coupled with other stud- ies are also being used to assess the extent of pathologic response of rectal cancers that receive neoadjuvant ther- apy.

Further studies are required on this use of PET scans before any definitive conclusions can be drawn.

The impact of PET in the preoperative staging and man- agement of rectal cancer patients has been studied by Heriot et al.

in a series of 46 patients who were assessed with PET scans at the time of their initial diagnosis. The surgical man- agement was changed for 17% of the patients because of pos- itive PET scan findings that upstaged the disease. These changes in management included canceling surgery and changing the field of administered radiation.

At the present time, PET scan is primarily used for the diagnosis of local and distant recurrence after curative surgery for colorectal cancer. It is also being used with increased fre- quency to detect distant metastasis of the time of the primary diagnosis of rectal cancer.

Immunoscintigraphy refers to the use of radiolabeled mon- oclonal antibodies that bind specifically to tumors to aid in detection and diagnosis. Most studies have primarily exam- ined patients with colon cancer or either colon and rectal can- cer. Few have examined primarily rectal cancer. The clinical application of this technique has been limited. Different mon- oclonal antibodies have been used, making it difficult to com- pare studies. The accuracy rate of immunoscintigraphy in detecting primary or metastatic colorectal cancers ranges from 63% to 96%.

There has not been a defined role for the use of preopera- tive or intraoperative radiolabeled immunoscintigraphy when dealing with a primary rectal cancer. Likewise, its role in management of recurrent rectal cancer has yet to be well defined. Intraoperatively, it may enhance the surgeon’s ability to assess both local and metastatic spread.

Conclusion

The accurate preoperative tumor staging is essential to select the best therapy for the rectal cancer patient. Presently, the depth of invasion and evidence of perirectal lymph node involvement is best assessed with ERUS. Abdominal and pelvic CT scanning or MRI are also important to detect extrarectal tumor spread and liver metastasis. A chest X-ray is also important to exclude pulmonary metastasis. The role of new imaging modalities such as PET in the staging of rectal cancer patients is currently under investigation.

T

29-7. Accuracy of ultrasound and CT scan in the preoperative diagnosis of liver metastasis from colorectal cancer

Ultrasound (%) CT (%)

Sheur et al., 1985

90 85

Gunven et al., 1985

66 80

Castaing et al., 1986

68 74

Gozzetti et al., 1986

80 74

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