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24 Colorectal Cancer: Preoperative Evaluation andStaging
ciency, an alternative is to obtain a non-contrast CT of the
chest with a gadolinium-enhanced MRI of the abdomen and
pelvis. Another alternative is positron emission tomography
(PET) with 2-[18F] uoro-2-deoxy-D-glucose (FDG) with
fused CT imaging (PET-CT), as discussed below [13].
In general, CT cannot accurately predict metastatic spread
to mesocolic or mesorectal lymph nodes. With regard to rectal tumors, CT cannot routinely determine depth of invasion
or mesorectal fascial involvement, primarily because CT is
unable to distinguish between tumor extension and peritumoral brosis. In addition, assessment of tumor involvement
of adjacent organs or the pelvic sidewall is often inaccurate.
The primary value of CT is its ability to detect distant
metastases.
PE T-C T
PET-CT is not generally recommended for initial staging of
colorectal cancers but may be used to assess equivocal ndings on CT scan, to rule out extrahepatic disease with established hepatic metastases when radical surgery is being
planned, to conrm features associated with a high risk of
metastases such as EMVI (extramural vascular invasion)on
MRI or high CEA levels, and in patients with a contraindication to intravenous contrast as previously mentioned [7].
FDG (udeoxyglucose) accumulates in malignant tumors as
well as in inammatory tissue and adenomas, thus is less
sensitive with a potential for false positives [13, 31], such as
in necrosis following radiation therapy. False negatives have
also been reported in mucinous tumors [13], because of the
relatively low cell/tumor volume ratio or any lesion <10mm.
437
Fig. 24.2 Endorectal ultrasound of T1 tumor. (Courtesy of Lehel
Somogyi, MD)
Rectal Cancer-Specic Staging Modalities
Appropriate staging is essential for rectal cancer, since many
current treatment algorithms are driven by estimates of tumor
stage. Accurate staging is paramount when considering neoadjuvant therapy, chance of future sphincter preservation,
and eligibility for clinical trials, including the choice of
denitive chemoradiotherapy (“watch and wait”) for complete clinical responders (see Chap. 28). Following clinical
staging, patients should be discussed at a multidisciplinary
tumor board consisting of surgeons, medical oncologists,
radiation oncologists, pathologists, and radiologists so that
the most efcacious recommendations can be made for each
individual patient.
Endorectal Ultrasound
Endorectal ultrasound (ERUS) and MRI are the main modalities used for local staging of a rectal cancer. ERUS involves
the insertion of a water-lled balloon into the patient’s rectum allowing a full circumferential view of the lumen. The
ve layers of the rectal wall are dened. These include (1)
the area between the balloon and the mucosa, (2) mucosa and
muscularis mucosa, (3) submucosa, (4) muscularis propria,
Fig. 24.3 Endorectal ultrasound of T3 tumor. (Courtesy of Lehel
Somogyi, MD)
and (5) the area between the muscularis propria and perirectal fat. Thus, theoretically, this modality is highly useful in
determining T stage since it is able to depict invasion of the
rectal wall layers (Fig. 24.2). It is technically challenging
due to the necessity of constantly having to adjust the angle
of the probe in relation to the rectal wall due to the presence
of clot or stool that may prevent its apposition to the rectal
mucosa. In addition, bulky tumors may constrict the lumen
and not allow for adequate balloon distention. As such, there
is a reported variation in the accuracy of ERUS in predicting
438
A. V. Hayman and C.-A. Vasilevsky
T stage ranging between 63% and 96% [32]. Although an
earlier published meta-analysis of 42 studies of 5000 patients
who underwent ERUS for rectal cancer staging found a
pooled sensitivity of 81–96% and specicity of 91–98% for
T stage [33], more recent data have shown a decline in T
stage accuracy ranging from 55% to 82% (Fig.24.3) [30].
Limitations of ERUS are that it is operator dependent; has
difculty differentiating between peritumoral inammation
versus desmoplastic reaction, especially after biopsy; and
thus has difculty in differentiating between a T2 tumor that
invades the muscularis propria from an early T3 with microscopic inltration of the perirectal fat, and some patients may
require a cathartic bowel preparation if enemas cannot clear
the rectum of stool [32]. Its advantage is that it may be able
to differentiate T1 from T2 tumors. ERUS has an accuracy of
73% for T1 lesions with a sensitivity of 71% and specicity
of 100% [34]. ERUS may also be able to stratify T1 tumors.
Sessile T1 lesions have been subdivided on the basis of the
depth of submucosal invasion into sm1 (slight submucosal
invasion), sm2 (intermediate between sm1 and sm3), and
sm3 (invasion into lamina propria) [35]. Since its main use is
in the differentiation between T1 and T2 tumors, ERUS
should be performed if local excision is being contemplated,
where local excision is considered appropriate for low risk
T1 cancers, but not favored for T2 cancers (see Chap. 27).
However, it may be difcult to during ERUS to visualize the
mesorectal fascia except at the level of the vagina or seminal
vesicles, and thus it is suboptimal for determination of the
predicted circumferential resection margin (CRM) when
performing standard mesorectal excision, which may be the
most important component of staging for locally advanced
tumors [36]. As current multimodality treatment of rectal
cancer mandates precise evaluation of the mesorectal fascia,
the major limitation of ERUS is its inability to accurately
dene it.
In assessment of nodal status, ERUS has been found to
have an accuracy of 75% (Fig.24.4). The main limitation in
assessing lymph nodes is the lack of criteria available to discriminate between malignant and inammatory nodes. The
5mm size criterion used to dene a malignant node has a
poor predictive value when compared to histology [37].
Rectal Cancer-Specic Pelvic MRI
High-resolution MRI is the recommended imaging modality
for accurate locoregional staging of rectal cancer. The standard rectal cancer MRI protocol includes thin-slice, high
spatial resolution T2-weighted images in order to encompass
the rectal tumor and the surrounding perirectal tissues and
mesorectum [30] obtaining images in three planes of view:
oblique axial perpendicular to the tumor; sagittal determined
by the longitudinal axis; and oblique coronal plane parallel
to the anal canal (Fig. 24.5a, b). The routine use of an
endorectal coil or endorectal contrast is not advised as its use
may stretch the rectum thus hindering accurate interpretation
of mural invasion. Although the addition of intravenous gadolinium contrast does not uniformly improve diagnostic
accuracy, several studies have demonstrated that the addition
of gadolinium resulted in the alteration of 24% of treatments
due to downstaging of T stage which obviated the need for
neoadjuvant treatment [38]. In addition, it may improve
detection of extramural vascular invasion (EMVI) [23]. MRI
provides information on tumor size, location, relation to the
sphincters and peritoneal reection, evidence of EMVI, and,
most importantly, on the predicted circumferential resection
margin (CRM). The CRM is the lateral or radial resection
margin and is dened as the closest distance of the tumor to
Fig. 24.4 Endorectal ultrasound of T3N1 tumor. (Courtesy of Lehel Somogyi, MD)
ab
24 Colorectal Cancer: Preoperative Evaluation andStaging
Fig. 24.5 MRI of a T4 tumor. (a). Axial and (b). sagittal T2 images show a bright, therefore mucinous, rectal cancer with direct invasion of the
right seminal vesicle (white arrow); black arrow shows the normal left seminal vesicle which is uid lled. (Courtesy of Vincent Pelsser, MD)
439
the mesorectal fascia. The CRM is considered to be positive
when the tumor extends within 1mm or less of the mesorectal fascia (Fig.24.6a–e). With neoadjuvant treatment, tumor
retraction from the CRM is regarded as an good prognostic
feature (Fig.24.7a–c) [36]. Local recurrence rates are higher
with positive CRM.MRI is superior to ERUS for assessing
the CRM because of its ability to identify the mesorectal fascia. MRI was found to have sensitivity for CRM involvement
of 77%, while specicity was 94% [39]. CRM assessment by
high-resolution MRI was the only preoperative variable that
signicantly predicted local recurrence, disease-free, and
overall survival in one study [40]. A negative CRM is associated with a 67% 5year survival versus 47% with a positive
CRM.
The accuracy of T stage has been found to improve with
increasing T stage (Fig.24.8a, b). However, as is the case
with ERUS, there is variability in the ability to discriminate between a T2 and an early T3 lesion, often misinterpreted so as to overstage the tumor [30]. Characterization
of T3 and T4 lesions has overall accuracy of nearly 100%
(Fig.24.9). High-quality MRI also allows for subclassication of T3 lesions (Fig.24.10). Although not mentioned
in the AJCC staging eighth edition or any TNM version,
the European Society for Medical Oncology (ESMO) subclassies T3 lesions based on depth of invasion from the
muscularis propria to the outer edge of the tumor into T3a
(<1 mm), T3b (1–5 mm), T3c (6–15 mm), and T3d
(>15mm) [26]. This subclassication has major potential
clinical applications since there are differences in recurrence and survival rates within the T3 category [41].
Moreover, this subclassication has the ability to better
risk stratify tumors, into need for neoadjuvant treatment
(for more advanced T3 lesion) versus upfront resection
with proctectomy alone (for early T3 lesions), a practice
that is more common in Europe than in North America.
The Canadian Quicksilver Trial, a prospective nonrandomized trial looking at the safety and feasibility of using MRI
criteria to identify patients with good prognostic rectal
cancer features, found that MRI criteria were able to select
patients who could undergo primary rectal cancer surgery
instead of initial chemoradiotherapy and achieve a low rate
of CRM positivity of 4.9% compared to 10% in historical
controls [42].
MRI is used primarily used to evaluate the relationship of
the tumor to the mesorectal fascia or other structures in close
proximity (i.e., any threatened radial margin), as well as to
the peritoneal reection, as this will predict oncologic prognosis [40]. Small T3 tumors of the upper rectum that are conned to the rectum and mesorectum alone may be amenable
to upfront resection, whereas in the converse situation (a
bulky upper rectal tumor that abuts the mesorectal fascia),
neoadjuvant radiotherapy is more likely to have a clinical
impact (Fig.24.11a–c). These nuances should guide neoadjuvant treatment decisions more than an arbitrary anatomic
delineation.
Low rectal cancers (dened as extending from the anal
verge to 6cm) are classied by MRI as extending to or below
the origin of the levators on the pelvic sidewall. An estimated
one-third of rectal cancers are low [43]; these tumors are
associated with relatively poor outcomes despite radical
operative procedures. This has prompted the creation of a
MRI-based staging system based on the relationship of the
440
ab
cd
A. V. Hayman and C.-A. Vasilevsky
e
Fig. 24.6 MRI of a T4 tumor with CRM involvement and subsequent
treatment regression. (a) Axial and (b) sagittal T2 images show an anterior T4 rectal cancer with direct invasion of the peripheral zone of the
prostate (white arrow). The primary tumor has intermediate signal on the
T2 sequence. (c) Axial T2 image shows extramural extension of the rectal
cancer with transgression the mesorectal fascia (CRM +) (white arrow).
(d) Axial T2 image shows multiple irregular mesorectal lymph nodes of
abnormal signal (N2– more than three nodes) (long white arrows) and
pelvic sidewall adenopathy (short white arrows). (e) Axial T2 image after
treatment shows good response of the tumor to therapy with profound T2
dark signal of the tumor from brosis (tumor regression grade 2) (white
arrow). Note the signicantly darker signal of the contracted tumor site
after treatment as opposed to the intermediate signal prior to therapy as
seen on image (a). (Courtesy of Vincent Pelsser, MD)
ab c
ab
24 Colorectal Cancer: Preoperative Evaluation andStaging
441
Fig. 24.7 MRI of T1/2 tumor with posttreatment regression. (a) Axial
and (b) coronal T2 images show a rectal tumor not extending beyond
the outer muscular layer (T1-T2 tumor) (white arrow). (c) Axial T2
image after treatment shows good response of the tumor to therapy with
profound T2 dark signal of the tumor from brosis (tumor regression
grade 2) (long white arrow); submucosal T2 bright signal is present
circumferentially from radiotherapy edema (short white arrow).
(Courtesy of Vincent Pelsser, MD)
Fig. 24.8 MRI of T1/2 tumor with with diffusion-weighted imaging. (a) Sagittal T2 image shows a muscle contained (T1-T2 tumor) focal rectal
cancer (white arrow). (b) with positive bright signal on axial diffusion imaging (white arrow). (Courtesy of Vincent Pelsser, MD)
tumor to the intersphincteric space and levators. More supercial tumors (T1 and 2) that have not invaded the intersphincteric plane are more likely to be resected with clear
CRM and thus require a less radical procedure as compared
to T3 and T4 tumors that have invaded the intersphincteric
space or levators. These tumors have an 18-fold increased
incidence of CRM involvement and often require extralevator abdominal perineal resection (ELAPE) or exenteration to
achieve clear margins.
The soft tissue contrast seen on MRI makes it an ideal
modality to identify mesorectal nodes (Fig. 24.12).
Morphological appearance of nodes has been found to be a
better discriminant of nodal involvement than size due to capsule disruption from tumor inltration, resulting in necrosis
within the node [30]. Using the criteria of irregular border and
mixed signal intensity, MRI-detected lymph node has been
reported to have a sensitivity of 85% and specicity of 97%.
A meta-analysis of 21 studies on the use of MRI for rectal
cancer, however, reported a sensitivity of 77% and specicity
of 71% for MRI-predicted lymph node involvement [39].
Rectal cancers assessed by MRI have been grouped
into: [30]
442
bc
A. V. Hayman and C.-A. Vasilevsky
• The “Good”: T1-T3a/b, N0, No EMVI, CRM clear; predicted local recurrence risk <10%
• The “Bad”: T3c/d-T4 or N1/2, CRM clear, predicted
local recurrence risk 10–20%
• The “Ugly”: threatened (<1 mm) or involved CRM,
EMVI present, low rectal cancer with involved intersphincteric plane or levators; local recurrence risk
>20%
MRI enables assessment of the pelvic side wall lymph
nodes (PSWLN), which is reported to be one of the reasons
for local recurrence, despite optimal surgery in the plane of
the mesorectum [according the principles of “total mesorectal excision” (TME)] especially in distal third cancers, which
spread along the internal iliac artery and then to the lateral
pelvic side wall [44]. Distal rectal cancers have been reported
to be associated with a 15% incidence of PSWLN compared
to 8% incidence in higher tumors [45].
Fig. 24.9 MRI of T3bN1 tumor. Axial T2 image shows a low rectal
cancer with focal extension beyond the outer muscular layer (T3b)
(long white arrow); positive mesorectal adenopathy (N1: three or fewer
nodes) is present posteriorly (short white arrow). (Courtesy of Vincent
Pelsser, MD)
a
Fig. 24.11 MRI of T3b tumor with posttreatment regression. (a) Axial
T2 image shows a rectal cancer with focal extension beyond the outer
muscular layer (T3b) (white arrow). (b) Axial T2 image after treatment
of a tumor shows T2 dark signal at the original tumor site from brosis
(tumor regression grade 2) (white arrow). (c) The same patient had a
Fig. 24.10 MRI of T3b tumor. Axial T2 image shows a rectal cancer
with focal extension beyond the outer muscular layer (T3b) (white
arrow). (Courtesy of Vincent Pelsser, MD)
left-sided T2 intermediate small mass (b) along the pelvis sidewall
(white arrow); diffusion imaging (c) was negative showing dark signal
(white arrow) indicating absence of tumor in this location, which was
subsequently conrmed by PET scan (images not shown) and stability
over time. (Courtesy of Vincent Pelsser, MD)
P
24 Colorectal Cancer: Preoperative Evaluation andStaging
443
A
CT:
Red arrow: Pathologic node
Yellow arrow: Would not be called a
pathologic node prospectively
R
Fig. 24.12 Diffusion-weighted MRI showing a positive and negative
mesorectal lymph node
Table 24.6 Performance of MRI at restaging (yMRI)
Sensitivity Specicity
yT 50.4% 91.2%
yN 76.5% 59.8%
yMRF 76.3% 85.9%
Table 24.7 Tumor regression grade (TRG) scale
mrTRG1 Complete response. No evidence of treated tumor
mTRG2 Good response. Dense brosis without obvious residual
mTRG3 Moderate response:>50% brosis or mucin along with
mTRG4 Slight response: small areas of brosis/mucin with
mTRG5 No response: no change in appearance or bulk from
tumor
intermediate intensity tumor
mostly tumor
original tumor
NOT FOR DIAGNOSIS
L
240 mm
The value of restaging MRI following neoadjuvant therapy
is controversial. For evaluation of the effects of neoadjuvant
treatment on the tumor, MRI with diffusion-weighted and
T2-weighted sequences has been suggested as an imaging
modality to reliably predict regression response with increased
sensitivity of 84% compared to 50% with T2 -weighted
sequences alone for evaluation of T stage. In terms of nodal
response, T2-weighted MRI is better to denote complete disappearance of nodes [46]. However, the performance of MRI for
restaging is lower than for the primary staging (see Table24.6).
Response of the tumor on MRI after neoadjuvant therapy
can be graded by comparing pre- and posttreatment MRIs
using the MR tumor regression grade (mrTRG) scale
(Table24.7), in which the relative amounts of viable tumor,
brosis, necrosis, and inammation are compared and classied. Some studies have demonstrated that MRI can predict
complete pathologic response with high accuracy; however,
results have not been uniformly reproduced (see Chap. 28).
Preoperative Evaluation
Prior to considering restorative proctectomy, baseline fecal,
urinary, and sexual function should be documented and the
risk of postoperative dysfunction discussed. As the vast
majority of patients undergoing proctectomy for rectal cancer will undergo creation of temporary or permanent intestinal stoma, the patient should be seen by an enterostomal
therapist for preoperative marking of an appropriate stoma
site and education. For any patient of child-bearing age, the
opportunities for sperm-banking or egg donation should be
discussed prior to any radiation treatment or operation (if no
neoadjuvant radiotherapy). If interested, they should be
expeditiously referred to reproductive endocrinologist and
infertility (REI) specialist. Patients with extensive comorbidities should be appropriately risk-stratied and optimized
perioperatively. Two online resources available via the
American College of Surgeons include the ACS NSQIP risk
calculator and the “Strong for Surgery” checklist [47, 48].
Optimizing and standardizing preoperative care given to
rectal cancer patients have been found to be associated with
better-quality pathologic specimens and decreased 30-day
morbidity [49]. A best practice preoperative checklist was
developed by the American Society of Colon and Rectal
Surgeons which outlines the measures necessary to optimize
patient care and improve outcomes in patients with rectal
cancer (Table24.8) [50]. Garnkle etal. looked at compli-
Table 24.8 ASCRS preoperative evaluation checklist
Formal pathology review was performed that conrmed invasive
carcinoma
In the unobstructed patient, a complete colonic evaluation was
performed
The tumor location within the rectum (distance from anal verge,
tumor length, anterior, posterior, left, right), as well as relationship
to levators and anorectal ring was documented
An assessment of family history, preoperative stool continence and
sexual function were documented
Clinical staging of the primary tumor (MRI+/−ERUS) was
performed
Clinical staging for distant metastases (chest, abdomen, pelvis) was
performed
Preoperative or perioperative CEA level was measured
Consideration of neoadjuvant treatment for > T2 or node positive
disease has been documented
Among those who received neoadjuvant treatment, the tumor was
restaged, and location was reconrmed just prior to operation
A multidisciplinary discussion of care, preferably during a formal
tumor board conference, was documented
If a stoma is considered, the site was preoperatively marked
444
A. V. Hayman and C.-A. Vasilevsky
ance with the preoperative checklist and found that compliance with the checklist was associated with improved
histologic and 30-day postoperative outcomes [50, 51]. In an
effort to standardize and improve the quality of rectal cancer
care, the American College of Surgeons Commission on
Cancer has developed the National Accreditation Program
for Rectal Cancer (NAPRC) which evaluated process and
procedure measures for patients who underwent proctectomy. The process measures included clinical staging completion, treatment starting fewer than 60days from diagnosis,
CEA level drawn before treatment, tumor regression, and
grading and margin assessment. The performance measures
included negative proximal, distal, and circumferential
margins and > or equal to 12 lymph nodes harvested during
resection [52].
Prognostic Factors Associated withOverall
andDisease-Free Survival
A combination of pathologic, clinical, and tumor-specic
characteristics allows for a better prediction of oncologic
outcome. A recent study of rectal cancer patients after surgical resection with curative intent found that patient age,
tumor regression grade, pathologic stage, extranodal tumor
deposits, and positive margins had the greatest impact on
overall and disease-free survival [53]. The presence of tumor
deposits was the strongest independent predictor of poorer
outcome. Patients who achieved complete pathologic
response after neoadjuvant treatment enjoyed signicant
improvement in overall and disease-free survival. A more
complete discussion of the various prognostic factors follows below.
Pathologic Features: Pre-Resection
Although it is clear that a well-performed surgical resection
(i.e., negative circumferential margins, complete mesorectal
or mesocolic excision) is the most important prognostic indicator for nonmetastatic colorectal cancers, tumor biologic
behavior also inuences the risk of recurrence and distant
metastasis and can inuence choice and duration of adjuvant
chemotherapy.
Poor pathologic features include lymphovascular invasion, perineural invasion, tumor budding, lymph node positivity and ratio, microsatellite stability, poorly differentiated
tumors, and adverse histologic type. These features can be
very inuential when determining the risk of local recurrence and/or lymphatic spread and are especially helpful for
stratifying risk when considering oncologic resection of
locally excised malignant polyps [54].
Lymphovascular Invasion (LVI)
LVI is a marker for possible lymph node involvement and is
identied when tumor cells are found around lymphatic channels, suggesting the tumor is in transit to regional lymph nodes.
When this feature is present in resected stage I or II colorectal
cancers, adjuvant chemotherapy should be considered.
Additionally, when found in malignant polyp specimens, this
would strengthen the recommendation for radical resection.
Perineural Invasion (PNI)
PNI refers to cancer involving the space surrounding a nerve.
While PNI has been associated with poor prognosis and a
high risk of recurrence, a recent single center study found that
prognosis was better in patients with PNI negative cancers.
PNI was found to be a signicant risk factor for recurrence
[55]. PNI has been found to be an independent prognosticator
over LVI and lymph node involvement in patients treated with
neoadjuvant treatment. It is hypothesized that tumor in the
perineural space around the rectum may be more radioresistant than tumor in lymphovascular spaces [56].
Tumor Budding
Tumor budding is a pathologic feature that is being increasingly used to stratify the risk of lymphatic spread and is especially clinically relevant for malignant polyps. (See Chap.
23.) Dened as the presence of tumor cells or clusters within
the stroma of the tumor (intratumoral budding) or at the
tumor edge (peritumoral budding), it is thought to represent
epithelial-mesenchymal transition and is associated with
worse prognosis. Tumor cell density indicates the relative
proportion of tumor cells to other constituents of the tumor
area. A lower tumor cell density has been found to be associated with poorer prognosis and is a strong predictor of lymph
node metastasis, lymphovascular invasion, local recurrence,
and poor disease-free survival. High tumor budding has been
found to be associated with an inltrative growth pattern and
lymphovascular invasion [57]. Clinically, it is similar to LVI/
PNI, suggesting that a more aggressive treatment approach
should be employed for these tumors [58, 59].
Mismatch Repair (MMR) Decient or
Microsatellite Instability-High (MSI) Status
It is now routine for all colorectal cancers to be evaluated for
genotypic evidence of Lynch syndrome, performing immunohistochemistry on biopsy specimens if possible, or resected
specimen at minimum, looking for absent expression of MMR
proteins and/or evaluation for MSI-high status (see Chap. 22).
Any MMR-decient (with normal BRAF) or MSI-high tumor
should prompt consideration of genetic counseling and/or
germline mutational analysis to assess for Lynch syndrome.
This may have immediate surgical implications (i.e., determining the extent of resection), as well as neoadjuvant or adju-
24 Colorectal Cancer: Preoperative Evaluation andStaging
445
vant treatment considerations (i.e., MSI- high tumors are less
responsive to 5U-based therapy). In addition, it will help risk
stratify at-risk relatives. The recent approval of immunotherapy (PD1 inhibitors) for metastatic, unresectable, or borderline resectable MSI-high tumors can have major treatment
implications for patients. Overall, MSI-high tumors carry a
better prognosis than MSI-low tumors, likely because they are
considered to be less aggressive overall, potentially due to an
improved host immune response to the tumor. This is despite
the fact that these tumors are often poorly differentiated and
that 5-uorouracil (5-FU)-based chemotherapy is less effective. (See Chap. 30.) However, it is likely that the lack of efcacy of 5-FU is due to the fact that these tumors have such a
better prognosis at baseline that chemotherapy is less able to
show a signicant effect [60].
Tumor Grade
Tumor grade is a stage-independent prognostic factor, with
undifferentiated or poorly differentiated tumors being associated with poorer prognosis than moderately or welldifferentiated tumors. This is considered to be a marker for
more aggressive tumors.
Histologic Type
Histologic types that are associated with worse prognoses
include mucinous, signet ring (>50% of the tumor contains
intracytoplasmic mucin), and adenosquamous. This is
thought to be due to the relative chemoresistance of these
predominantly acellular tumors.
MSI-H tumors due to the immune response linked to the
lymphocytic inltrate.
The importance of lymph node ratio (LNR), the ratio of
metastatic nodes to the total number of nodes harvested, has
been highlighted as a prognostic tool with a lower LNR associated with a better prognosis. Increasing LNR has been
found to be an independent predictor of decreased overall
and disease-free survival [64]. In fact, the IDEA trial demonstrated that for patients with adequate LNH and low lymph
node positivity (1 or 2), a reduced duration of 3 versus
6months of FOLFOX chemotherapy had equivalent oncologic outcomes with less morbidity [65].
Extranodal Tumor Deposits
Extranodal tumor deposits are irregular discrete tumor
deposits found in the pericolonic or perirectal fat or in adjacent mesentery away from the leading edge of the tumor
within the lymphatic drainage area of the primary tumor, but
not associated with a lymph node. Most are thought to be due
to LVI or PNI but are not counted as lymph nodes replaced
by tumor. The presence of extranodal tumor deposits is associated with relatively poor survival. Tumors with comparable
T stage and without satellite nodules have been found to have
higher 5-year survival rates compared to the same T stage
with nodules (2% vs 37% p<0.0001) [66]. Moreover, the
presence of tumor deposits has been associated with
decreased survival following neoadjuvant therapy [67].
Pathologic Factors: Post-Resection
Lymph Node Positivity andRatio
Guidelines have acknowledged that the minimum acceptable number of lymph nodes for accurate staging is 12. An
association between lymph node harvest (LNH) and survival has been demonstrated, and it has been suggested that
patients in stage II disease with a lower LNH have a worse
prognosis [61]. The number of retrieved lymph nodes often
falls short of the recommended 12. Factors that may be
responsible include patient age, body mass index, tumor
location, neoadjuvant therapy, surgical technique, and the
pathologists’ assessment. LNH is often intrinsically less
with age (possibly due to a weaker immune response to the
tumor) and tumor location in the rectum. Furthermore, the
number of lymph nodes retrieved following neoadjuvant
treatment is often less than what is retrieved after surgery
alone, likely due to the effect of radiation on the lymphatic
system [62]. Retrieval of fewer nodes may, in fact, be a
marker of higher tumor response and better prognosis following neoadjuvant treatment [63]. LNH is enhanced in
Mesorectal Grade
The quality of mesorectal excision has been shown to be an
independent factor of local and overall recurrence.
Perforation of the rectum during surgery is also associated
with poor prognosis and should be recorded as pT4 [68, 69].
It has also been suggested that mesorectal grade correlates
inversely with size of the tumor, i.e., perforation during surgery or incomplete excision may occur more often during
excision of large, bulky, locally advanced tumors with extensive brosis.
Tumor Regression Score
As neoadjuvant therapy has become the standard of care for
many rectal cancers, the size of viable tumor remaining is a
measure of the effectiveness of therapy, with the absence of
Table 24.9 Tumor regression score
Tumor regression score Description
0 Complete response
1 Near-complete response
2 Partial response
3 Poor or no response
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A. V. Hayman and C.-A. Vasilevsky
viable tumor and minimal residual disease being associated
with better outcome [70]. Complete pathologic response following treatment is associated with a favorable prognosis
[25]. A tumor regression score is used to assess the response
of the tumor and not the nodes (Table24.9) [70].
Clinical or Imaging-Based Factors
Age
Younger age (<45) at presentation has been associated with
poor prognosis overall, possibly due to the presence of
adverse prognostic features and advanced tumor stage at
diagnosis. However, after controlling for disease stage,
patient, and treatment factors, prognosis may be more favorable in younger patients since these patients can be treated
more aggressively [71]. Also, advanced age is often associated with frailty which may limit the ability to tolerate chemotherapy or chemoradiotherapy.
Older patients also have worse baseline bowel dysfunction and continence. Therefore, older patients with rectal
cancer are often not good candidates for restorative proctectomy with low colorectal or coloanal anastomosis, nor do
older patients tolerate temporary diverting ileostomy well
due to the reduced drive to drink uids with age and
increased risk of dehydration. Therefore, frail patients with
rectal cancer but without a threatened CRM should be considered for upfront nonrestorative proctectomy, Hartmann
resection, or abdominoperineal resection, depending on
location of the tumor relative to the pelvic oor. If there is
concern for a threatened radial margin, another option is
neoadjuvant short-course radiotherapy (4–5Gy for 5days,
for a total of 20–25Gy) followed by resection. Neoadjuvant
short-course radiotherapy is better tolerated than longcourse chemoradiotherapy and has shown equivalent oncologic outcomes [72].
Extramural Vascular Invasion (EMVI)
EMVI is a strong predictor of poor prognosis which, as
previously mentioned, can be predicted on prestaging
MRI.EMVI is defined as the presence of tumor cells in
the microvasculature beyond the muscularis propria and
is more prevalent in locally advanced T3/T4 lesions,
although it may be present with early stage tumors as
well [30]. Histologically confirmed EMVI has been associated with a higher risk of local recurrence and poorer
survival regardless of nodal status or depth of mural invasion. The incidence of EMVI ranges from 9% to 61%
[73]. Brown has described MRI- directed EMVI grading
system which is able to predict histologic EMVI with a
high specificity ranging between 88% and 96% but with
low sensitivity of 29–62% due to the inability to accurately visualize small caliber vessels. MRI evaluation of
EMVI has been suggested by some authors to be more
accurate than histologic assessment [74]. MRI- detected
EMVI predicts both risk of recurrence, as well as synchronous metastases [34, 75]. MRI-detected EMVI was
also associated with a fourfold risk of developing metachronous metastases within 1 year of diagnosis [76].
Thus the presence of EMVI on MRI may signify tumor
embolization into the systemic circulation. Therefore,
even for T1 or T2 tumors, patients with MRI-detected
EMVI should be considered for chemotherapy to improve
distant control [73].
Circumferential Radial Margin (CRM) Status
In addition to locally advanced tumors (T3/T4), other factors
predictive of CRM involvement include tumor <4cm from
the anal verge, anterior quadrant invasion, and EMVI [77].
The presence of all four features predicts a risk of incomplete resection as high as 60%. These patients may benet
from total neoadjuvant therapy with radiotherapy and multidrug systemic chemotherapy prior to resection.
The NCCN recommends neoadjuvant treatment for all
clinical stage II (cT3/T4; N0) and clinical stage III (any cT;
N1/2) rectal cancers [78], but this includes a heterogeneous
group of patients, some of whom may be overtreated. As a
result, the UK and ESMO have shifted their treatment
decision- making from being based purely on TNM to one
that is guided by MRI ndings. This allows personalized rectal cancer management based on selective MRI criteria in
order to minimize the risks of over- and undertreatment,
based on the risk of local recurrence [30].
An involved CRM increases the risk of local recurrence and mortality with both colon and rectal tumors.
Although more commonly associated with a discussion on
rectal cancer, the radial margin of the colon is formed by
its mesenteric attachment point along with the cut edge of
nonserosalized or retroperitoneal segments at the time of
colon resection. Radial margin positivity is associated
with multivisceral resection and conversion from laparoscopic to open resection and is a stage-independent outcome predictor strongly associated with recurrence and
shorter survival [79]. Even with complete mesocolic excision, a radial margin <1mm was found to be an independent predictor of survival and recurrence [80]. Russell
et al. used a cancer-predictive mode [81] that included
older age, male sex, African-American race, as well as
advanced AJCC stage especially T stage, signet ring his-