Review Article
Dig Dis 1999;17:67–79
Pathology Report in Colon Cancer:
What Is Prognostically Important?
Carolyn C. Compton
Department of Pathology, Massachusetts General Hospital, Boston, Mass., USA
Key Words
TNM · Prognostic factors · Stage · Grade · Pathology
Abstract
Surgical resection is the primary treatment modality
for colorectal cancer, and the most powerful tool for
assessing prognosis following surgery is pathologic
analysis of the resection specimen. Although the para-
meters that determine the pathologic stage are the
strongest predictors of postoperative outcome, a num-
ber of additional pathologic features have prognostic
significance that is independent of stage. These include:
histologic grade; small vessel (lymphatic or venular)
invasion; extramural venous invasion; perineural inva-
sion; tumor border configuration; host lymphoid re-
sponse to tumor, and the status of surgical margins. For
specimens in which the radial (circumferential) margin
is applicable, surgical clearance around the tumor is
also of import. It is self-evident that, compared to data
derived from additional assays, prognostic information
that can be derived directly from standard histologic
sections of a tumor is of the greatest cost-benefit to
the patient. In the current era of cost containment, it is
essential that surgical pathologists evaluate and report
the pathologic features that are of prognostic and/or
predictive significance in every case of colorectal cancer
and, in turn, that the import of these be understood by
the treating physicians.
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Introduction
Pathologic evaluation is a critical component in the
management of patients with colorectal cancer, from ini-
tial diagnosis through definitive treatment, and patho-
logic assessment of a resected colorectal cancer is still
considered the most accurate method of assessing the
tumor-related features that determine postoperative out-
come. Pathologic staging is the single most powerful pro-
gnostic indicator in colorectal cancer, and in many cases,
it also determines the appropriateness of adjuvant treat-
ment. In addition, numerous additional pathologic fea-
tures have been shown to have prognostic significance
that is independent of stage and may help to further
substratify tumors of like stage. This is true whether the
specimen is an endoscopically removed malignant polyp
or a surgically resected carcinoma. Unfortunately, how-
ever, neither the features that determine the pathologic
stage, the ground rules that define the interpretation of
these features, nor the prognostic importance of addi-
tional gross and histopathologic features itemized in the
pathology report are always universally understood. This
review delineates the pathologic features of colorectal
cancers that have direct bearing on patient care and that
are essential elements of the pathology-related tumor data
collected by tumor registries. In addition, the pathologic
features that have prognostic significance, either favorable
or unfavorable, are discussed and are distinguished from
those with no independent impact on outcome.
In colorectal cancer, as in most other diseases, the
accuracy and completeness of a pathologic evaluation
Dr. Carolyn C. Compton
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Department of Pathology, Warren 256
Massachusetts General Hospital
55 Fruit Street, Boston, MA 02114 (USA)
Tel. +1 617 726 6875, Fax +1 617 720 0215, E-Mail compton.carolyn@mgh.harvard.edu
Göteborgs Universitet
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may depend in part on the pathologist’s awareness of
pertinent clinical and operative data. The principal re-
sponsibility for providing clinical information lies with
the referring clinician(s). The referring clinician may also
need to orient the resection specimen or indicate anatomic
areas of special concern related to intraoperative findings.
Requisition forms for pathology are designed to accom-
modate such clinical information and can often be used as
the basic means of communication with the pathologist.
Pathologic Evaluation of Malignant Polyps
Diagnosis and treatment of colon cancers by endo-
scopic polypectomy has become commonplace. Often,
malignant polyps are unsuspected at endoscopy and are
revealed on microscopic examination. ‘Malignant polyps’
are defined as adenomas containing carcinoma that in-
vades through the muscularis mucosae into the submu-
cosa, regardless of the overall proportion of the adenoma
that is replaced by cancer. They encompass both polypoid
carcinomas in which the entire polyp head is replaced
by carcinoma and adenomas with focal or multifocal
malignancy. By convention, malignant polyps exclude ad-
enomas containing either ‘intraepithelial carcinoma’ or
‘intramucosal carcinoma’ because these incipient malig-
nancies possess no biological potential for metastasis (see
‘Definition of pTis’ below). ‘Intraepithelial carcinoma’ is
defined as cytologically malignant cells, with or without
evidence of stromal contact-independent growth (e.g.
solid growth or cribiforming) that do not invade the lam-
ina propria of the polyp mucosa. All malignant cells
remain on the epithelial side of the basement membrane
of the neoplastic gland in which they reside. Some pa-
thologists include severe or high-grade dysplasia in the
category of intraepithelial carcinoma. ‘Intramucosal car-
cinoma’ is defined as malignant cells that invade through
the basement membrane of their gland of origin and
invade the lamina propria up to and including the muscu-
laris mucosae. Thus, in malignant polyps, carcinoma ex-
tends through the muscularis mucosae into submucosa
(also known as ‘invasive’ malignancy to differentiate it
from intraepithelial or intramucosal malignancy). Polyps
containing invasive malignancy represent approximately
5% of all adenomas [1, 2], and the chance that any given
adenoma will contain an invasive malignancy increases
with polyp size. The incidence of invasive carcinoma in
adenomas of any histologic type that are greater than
2 cm in size ranges from 35 to 53% [3], with villous ade-
nomas having a higher incidence than tubular adenomas
68 Dig Dis 1999;17:67–79
of equal size. Therefore, on pathologic examination, any
polyp 2 cm or greater in size is approached with the
suspicion that it might harbor an invasive cancer.
The histopathologic evaluation of malignant polyps
removed endoscopically is critical and directly affects the
clinical management of the patient [4]. Although malig-
nant polyps constitute a form of ‘early colorectal carci-
noma’ that may be cured by endoscopic polypectomy
alone [4–6], the incidence of an unfavorable outcome
following polypectomy (i.e. lymph node metastasis or
local recurrence from residual malignancy) varies from
about 10 to 20% [7, 8]. Histopathologic features that have
been shown to significantly increase the risk of adverse
outcome include all of the following [9–18]: (1) high tumor
grade (i.e. poorly differentiated or undifferentiated carci-
noma); (2) tumor at or =1 mm from the polyp resection
margin, and (3) lymphatic or venous (small vessel) vessel
involvement by tumor.
In the presence of one or more of these features, the
estimated risk of an adverse outcome following poly-
pectomy alone has been estimated to be about 10–25%
[7, 10, 19–21]. Therefore, if one or more high-risk features
are found on pathologic examination of a resected polyp,
further therapy may be required. Optimal management is
decided on an individual case basis [22], but segmental re-
section of the involved colonic segment, local excision (e.g.
transanal disk excision for a low rectal lesion), or radiation
therapy may be considered. In the absence of high-risk fea-
tures, the chance of an adverse outcome is extremely small,
and polypectomy alone is considered curative.
In the pathologic assessment of malignant polyps, in-
terobserver variability is greatest in relation to small vessel
invasion [8]. An absolute diagnosis of lymphatic or venu-
lar invasion is dependent upon finding carcinoma cells
within an endothelial-lined space. Contraction artifact in
the tissue, tumor-induced stromal sclerosis, and extracel-
lular mucin pools produced by the cancer may all com-
plicate the evaluation of vessel invasion. Examination of
additional tissue levels of the specimen, review by a se-
cond observer, and/or immunohistochemical staining for
endothelial markers (e.g. factor VIII or CD34) may or
may not help to resolve the dilemma but are documented
in the pathology report when performed. Due to these
difficulties, small vessel invasion may be impossible to
diagnose definitively in some cases and, ultimately, may
be judged as being indeterminate or suspicious. It is note-
worthy that in many published cases in which lymphatic
invasion was judged (on blinded review) as indeterminate
because of interobserver disagreement, the patients went
on to die of their disease following polypectomy alone
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[8]. Thus, even the suspicion of small vessel invasion in
malignant polyps may be regarded as ominous.
Pathologic Evaluation and Staging of Surgically
Resected Colorectal Cancers
The pathology report of a colorectal cancer resection
specimen should always include the anatomic site of the
malignancy, the histologic type, the parameters that deter-
mine the local tumor stage, and the histopathologic docu-
mentation of distant metastasis, if applicable. Other
features that are reported include those that have addi-
tional prognostic or predictive value as well as those that
may be important for clinicopathologic correlation or
quality control (e.g. actual tumor size vs. size measure-
ment by imaging techniques). The essential pathologic
features of a colorectal cancer and the clinical significance
of these findings are discussed individually below.
Anatomic Site of the Tumor
Documentation of the exact anatomic location of a
colorectal carcinoma is a fundamental part of the patho-
logic assessment and is performed as part of the ‘gross’
or ‘macroscopic’ examination of the specimen. Due to
distortion of the anatomy by tumor and/or lack of ana-
tomic landmarks that make it possible to differentiate the
proximal from the distal end of the resected segment,
orientation of the specimen may be difficult in some cases,
and assistance from the surgeon may be required.
Typically, the anatomic site of the tumor is docu-
mented by measurement from known landmarks accord-
ing to general guidelines defining colonic topography.
Clinical data may also be helpful in establishing the tumor
site in many cases. In general, four major anatomic divi-
sions of the colon are recognized: the right (ascending)
colon, the middle (transverse) colon, the left (descending)
colon, and the sigmoid colon. The right colon is sub-
divided into the cecum (often peritoneally located and
measuring about 6¶9 cm) and the ascending colon
(retroperitoneally located and measuring 15–20 cm long).
The descending colon, also located retroperitoneally, is
10–15 cm in length. The descending colon becomes the
sigmoid colon at the origin of the mesosigmoid, and the
sigmoid colon becomes the rectum at the termination of
the mesosigmoid. The upper third of the rectosigmoid
segment is covered by peritoneum on the front and both
sides. The middle third is covered by peritoneum only on
the anterior surface. The lower third (also known as the
rectum or rectal ampulla) has no peritoneal covering [23].
Pathology Report in Colon Cancer
The rectum is defined clinically as the distal large intestine
commencing opposite the sacral promontory and ending
at the upper border of the anal canal. When measuring
below with a rigid sigmoidoscope, it exends 16 cm from
the anal verge. A tumor is classified as rectal if its inferior
margin lies less than 16 cm from the anal verge or if any
part of the tumor is located at least partly within the
supply of the superior rectal artery [24].
Additional guidelines for assigning a tumor site have
been established by the American Joint Committee on
Cancer (AJCC) [23]. Tumors located at the border be-
tween two subsites of the colon (e.g. cecum and ascending
colon) are registered as tumors of the subsite that is more
involved. If two subsites are involved to the same extent,
the tumor is classified as an ‘overlapping’ lesion. Tumors
may also be classified as overlapping when the anatomic
distinction between two subsites is precluded due to
tumor distortion of the anatomy. For example, a tumor
may be classified as rectosigmoid when differentiation
between the rectum and sigmoid according to the above
guidelines is not possible [25].
Tumor Size
The tumor dimensions (three) as recorded by the
pathologist on the gross examination of the specimen is
considered the definitive determination of tumor size. It
is recorded as an element of tumor documentation, but
tumor size is not related to outcome. Eight separate stud-
ies have shown tumor size to be of no prognostic signifi-
cance in colorectal cancer [26–33].
Tumor Configuration
Tumor configuration is usually recorded as exophytic
(fungating), endophytic (ulcerative), diffusely infiltrative
(linitis plastica), or annular, but overlap among these
types is common. Exophytic growth may be further de-
fined as pedunculated or sessile. Most studies have either
failed to demonstrate an independent influence of gross
tumor configuration on prognosis or the association has
proven controversial. In three studies, exophytic growth
has proven to be an adverse prognostic factor on multi-
variate analysis [34–36]. However, other studies have
either failed to demonstrate prognostic significance for
gross tumor morphology [31, 37] or failed to confirm its
significance on multivariate analysis [38]. The uncommon
linitis plastica type of tumor configuration has been
shown to be associated with an unfavorable prognosis
[39], but the prognostic import may be related primarily
to the high grade (see ‘Tumor Grade’ below) of carcino-
mas that typically exhibit this gross morphology.
Dig Dis 1999;17:67–79 69
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Table 1. World Health Organization classification of colorectal carci-
noma [41] 1
Adenocarcinoma in situ/severe dysplasia
Adenocarcinoma
Mucinous (colloid) adenocarcinoma (?50% mucinous)
Signet-ring cell carcinoma (?50% signet-ring cells)2
Squamous cell (epidermoid) carcinoma
Adenosquamous carcinoma
Small-cell (oat cell) carcinoma3
Undifferentiated carcinoma3
Other (specify)
1
The term ‘carcinoma, NOS’ (not otherwise specified) is not part
of the WHO classification.
2
Signet ring cell carcinomas are defined as poorly differentiated
and assigned grade 3/4.
3
Small cell carcinomas and undifferentiated (histologic type) carci-
nomas are assigned grade 4/4.
Histologic Type
For consistency and uniformity in reporting, the inter-
nationally accepted histologic classification of colorectal
carcinomas proposed by the World Health Organization
(table 1) is recommended by the College of American
Pathologists and is usually used in pathology reports
[40, 41]. A histologic type is always designated in the patho-
logy report, but it has little, if any, clinical significance.
Aside from those histologic types that are always classified
as poorly differentiated or undifferentiated (i.e. high
grade), histologic type has been shown repeatedly to lack
independent prognostic significance [31, 32, 35, 36, 38, 42–
49]. Only a few studies have indicated a significant associ-
ation of mucinous adenocarcinoma with adverse outcome,
but these have been largely limited to univariate analyses
[49–52]. In two studies, an adverse association could be
demonstrated only for specific anatomic regions of the
bowel (e.g. the rectosigmoid [50, 52]) or for specific subsets
of patients (i.e. those =45 years of age [53]). In other stud-
ies, mucinous carcinomas and signet ring cell carcinomas
have been jointly evaluated in contrast to typical adenocar-
cinoma and found to have an adverse effect on prognosis
[54–56], a finding probably related mainly to the signet ring
cell carcinomas included in the analysis. A single multivari-
ate analysis has shown mucinous carcinoma to be an inde-
pendent predictor of adverse outcome, but this study was
limited to tumors presenting with large bowel obstruction,
itself an adverse prognostic factor [30]. Overall, therefore,
it must be concluded that the histologic types of colorectal
cancer, aside from those conventionally designated as high
grade, are of no prognostic import.
70 Dig Dis 1999;17:67–79
Tumor Grade
A number of grading systems for colorectal carcinoma
have been proposed in the literature, but a single widely
accepted, uniformly employed standard for grading is still
lacking. Among the suggested grading schemas, both the
number of grades and the criteria for distinguishing
among them have varied markedly. In some systems,
grade is defined on the basis of a single microscopic
feature, such as the degree of gland formation. In other
systems, a large number of histopathologic features are
included in the evaluation. Regardless of the complexity
of the criteria, however, most systems stratify tumors into
three or four grades as follows: grade 1>well-differenti-
ated; grade 2>moderately differentiated; grade 3>
poorly differentiated, and grade 4>undifferentiated.
Even if adherence to a specific grading system is prac-
ticed, normally encountered variations in the appearance
of individual histologic features may make implementa-
tion of even the simplest grading systems problematic.
Ultimately, therefore, histologic grading is largely subjec-
tive and is associated with a significant degree of interob-
server variability [57, 58]. Despite these issues, histologic
grade has repeatedly been shown to be an independent
prognostic factor on multivariate analysis [26, 27, 29–31,
34, 37, 44, 47, 59–63]. Specifically, it has been demon-
strated that high tumor grade is an adverse prognostic
factor. In the vast majority of studies documenting the
prognostic power of tumor grade, however, the number of
grades has been collapsed, and a two-tiered stratification
schema (i.e. high grade and low grade) has been employed
for data analysis. In the two-tiered systems, low grade
has included both well-differentiated and moderately
differentiated adenocarcinomas, and high grade has in-
cluded poorly differentiated and undifferentiated cancers.
In general practice, a two-tiered grading system would
also be expected to reduce interobserver variability, since
the widest variations in grading occur with stratification
of low-grade tumors into well- or moderately differenti-
ated categories [57]. Diagnosis of poorly differentiated or
undifferentiated tumors is more consistent, and interob-
server variability is relatively small [57]. In light of its
proven prognostic value as well as its relative simplicity
and reproducibility, the use of a two-tiered grading system
for colorectal carcinoma would be advisable but, unfortu-
nately, is not common practice. Therefore, to help reduce
subjectivity and interobserver variation in applying the
usual four-tiered grading system, the College of American
Pathologists has suggested a semiquantitative evaluation
schema as follows [40]: grade 1>well-differentiated
(?95% of tumor composed of glands); grade 2>moder-
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Table 2. Definitions of TNM categories and stage groupings [23] nodes, metastasis) Staging System of the AJCC and the
International Union Against Cancer (UICC) is recom-
Primary tumor (T) mended by the College of American Pathologists [23, 40,
T0 No evidence of primary tumor
64]. The TNM system is widely used by national, regional,
Tis Carcinoma in situ (intraepithelial or intramucosal carcinoma)
T1 Tumor invades the submucosa
and local tumor registries in the United States, and it is
T2 Tumor invades the muscularis propria internationally accepted.
T3 Tumor invades through the muscularis propria into the In the TNM system, the designation ‘T’ refers to the
subserosa or into the nonperitonealized pericolic or first resection of a primary tumor. The designation ‘N’
perirectal tissues1 refers to the status of the regional lymph nodes, and ‘M’
T4 Tumor directly invades other organs or structures (T4a) refers to distant metastatic disease. The symbol ‘p’ refers
or perforates the visceral peritoneum (T4b)
to the pathologic classification of the TNM (e.g. pT1),
Regional lymph nodes (N) as opposed to the clinical classification, designated by
N0 No regional lymph node metastasis the symbol ‘c’ (e.g. cT1). Pathologic classification is based
N1 Metastasis in 1–3 lymph nodes
on gross and microscopic examination. Determination of
N2 Metastasis in 4 or more lymph nodes
pT entails a resection of the primary tumor or biopsy
Distant metastasis (M) adequate to evaluate the highest pT category; pN entails
M0 No distant metastasis removal of nodes adequate to validate lymph node metas-
M1 Distant metastasis
tasis, and pM implies microscopic examination of distant
TNM stage groupings Modified Astler-Coller stage lesions. Clinical classification (cTNM) is usually deter-
Stage 0 Tis N0 M0 Stage A mined by imaging techniques carried out before treatment
Stage I T1 N0 M0 N/A during initial evaluation of the patient or when pathologic
T2 N0 M0 Stage B1 classification is not possible [23]. It is the grouping of a
Stage II T3 N0 M0 Stage B2 T, N, and M parameter that determines the stage of the
T4 N0 M0 Stage B3 tumor and relates to prognosis. Thus, the term ‘stage’ in
Stage III Any T N1 M0 Stage C1 (T2); C2 (T3); C3 (T4)
reference to an individual TNM category is inappropriate
Any T N2 M0 Stage C1 (T2); C2 (T3); C3 (T4)
Stage IV Any T Any N M1 Stage D
(e.g. ‘T stage’). A TNM stage grouping can be constructed
using a combination of clinically derived and pathologi-
1
Optional expansion of T3: cally derived data (e.g. pT1, cN0, cM0). However, by
pT3a>minimal invasion: =1 mm beyond the border of the mus- convention, when pathologic data become available, it
cularis propria. automatically replaces the respective clinically deter-
pT3b>slight invasion: 1–5 mm beyond the border of the muscu- mined category. This practice is based on the assumption
laris propria.
that pathologically derived data are more accurate.
pT3c>moderate invasion:?5–15 mm beyond the border of the
muscularis propria.
The definitions of the individual TNM categories and
pT3d>extensive invasion:?15 mm beyond the border of the mus- the TNM stage groupings for colorectal carcinoma are
cularis propria. shown in table 2, and correlation with the often used
Astler-Coller modification of the Duke’s staging system
is also shown. The 5-year survival rates for the five TNM
stages are as follows [65, 66]:
ately differentiated (50–95% of tumor composed of
glands); grade 3>poorly differentiated (5–49% of tumor
composed of glands), and grade 4>undifferentiated Stage 0, I (Tis, T1; N0; M0) ?90%*
(=5% of tumor composed of glands). Stage I (T1; N0; M0) 80–85%*
Stage II (T3, T4; N0; M0) 70–75%*
Stage III (T2; N1–3; M0) 70–75%
Pathologic Stage Stage III (T3; N1–3; M0) 50–65%*
The best estimation of prognosis in colorectal cancer Stage III (T4; N1–3; M0) 25–45%*
is related to the anatomic extent of disease determined Stage IV (M1) =3%
on pathologic examination of the resection specimen (i.e.
the pathologic stage of the tumor) [39]. Although a large
number of staging systems have been developed for co- The individual parameters of the TNM categories are
lorectal cancer over the years, use of the TNM (tumor, discussed in detail below.

Pathology Report in Colon Cancer Dig Dis 1999;17:67–79 71

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 Definition of pTis
For colorectal carcinomas, carcinoma in situ (pTis)
includes both intraepithelial and intramucosal carcinoma
(see ‘Pathologic Evaluation of Malignant Polyps’ above).
Only with penetration of the muscularis mucosae and
infiltration of the submucosa is the tumor classified as
an invasive malignancy and categorized as pT1. This
definition of pTis is unique to the colon and rectum.
In reference to all other epithelial systems, pathologists
reserve the term ‘carcinoma in situ’ for intraepithelial
malignancy alone and may use the term synonymously
with ‘high grade dysplasia’ or ‘severe dysplasia’. Similarly,
for carcinomas of all organs except the large intestine,
the term ‘invasive’ refers to stromal infiltration of any
degree and connotes possible access of tumor cells to
stromal lymphatics or blood vessels with a consequent
risk of metastasis. Only in the colon does pTis encompass
cancers that have invaded the mucosal stroma. This is
justified because the colonic mucosa is anatomically
unique in that it lacks stromal lymphatics and tumor
invasion of the lamina propria has no associated risk of
regional nodal metastasis. Nevertheless, use of the term
‘carcinoma in situ’ with reference to colorectal tumors
can be confusing, depending upon whether it is used to
refer to the staging parameter pTis or only to the specific
histologic feature of intraepithelial carcinoma. For this
reason, it is recommended that ‘intraepithelial carcinoma’
and ‘intramucosal carcinoma’ be used for pathologic de-
scription of colorectal tumors in the pTis category.
Optional Expansion of pT3
The extent of extramural invasion has been reported
to influence prognosis adversely, whether or not regional
lymph node metastasis is present, and an optional expan-
sion pT3 has been proposed as shown in table 2 [25].
Extramural extension is measured from the external sur-
face of the muscularis propria to the point of deepest
penetration of the tumor into the extramural soft tissue.
The data suggest that the critical depth of penetration
with a significant effect on prognosis is 5 mm. Therefore,
reporting of pT3 tumors as extending p5 or ?5 mm
beyond the wall may be justified [25]. Extramural exten-
sion of the tumor within lymphatics or veins does not
count as local spread of tumor as defined by pT3 [25].
Subclassification of pT4
The highest category of local extent of colorectal
tumor, pT4, is defined by extension into an adjacent struc-
ture or organ or penetration of the parietal peritoneum.
A free perforation of a colorectal carcinoma into the
72 Dig Dis 1999;17:67–79
peritoneal cavity is also classified as T4b [25]. Serosal
penetration is a dire feature. A number of large studies
that have evaluated serosal penetration as an independent
pathologic variable have demonstrated by multivariate
analysis that it has a strong negative impact on prognosis
[26, 31, 67, 68]. The median survival time following surgi-
cal resection for cure is significantly shorter with pT4
tumors that penetrate the visceral peritoneum compared
with pT4 tumors without serosal involvement, with or
without distant metastasis, as shown below [25]. A more
recent study on the importance of local peritoneal in-
volvement in curative resections by Shephered et al. [67]
has even suggested that the prognostic power of this fea-
ture may supersede that of regional lymph node status
(N category).
5-Year survival rate Median survival time
% months
pT4a, M0 49 58.2
pT4b, M0 43 46.2
pT4a, M1 12 22.7
pT4b, M1 0 15.5
Unfortunately, histological determination of serosal
penetration is often problematic and may be under-
diagnosed by histopathologic assessment for several rea-
sons. Documentation of peritoneal involvement by the
tumor demands meticulous pathologic analysis. It may
require extensive sampling and/or serial sectioning and
can be missed on routine histopathologic examination, a
fact that thas been emphasized in the literature. It has
been shown that cytologic examination of serosal scrap-
ings reveals malignant cells in as many as 26% of tumor
specimens categorized as pT3 by histologic examination
alone [67, 69]. In addition, the histopathologic findings
associated with peritoneal involvement by the tumor are
heterogeneous, and standard guidelines for their diag-
nostic interpretation are lacking. Thus, interobserver vari-
ability in the diagnosis of peritoneal penetration may be
substantial. Since most pathologists tend to err on the
side of conservative interpretation, underdiagnosis of this
feature is likely.
In a study by Shephered et al. [67], the spectrum of
microscopic features that may be seen with local perito-
neal involvement by a tumor was recognized and specifi-
cally addressed. Three types of local peritoneal involve-
ment were defined and analyzed separately: (1) mesothe-
lial inflammatory and/or hyperplastic reactions with
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tumor close to, but not at, the serosal surface; (2) tumor
present at the serosal surface with inflammatory reaction,
mesothelial hyperplasia, and/or erosion/ulceration, and
(3) free tumor cells on the serosal surface (in the perito-
neum) with underlying ulceration of the visceral perito-
neum. All three types of local peritoneal involvement
were associated with decreased survival, whereas a tumor
well clear of the serosa had no independent adverse effect
on prognosis.
Direct invasion of other organs or structures, pT4a,
includes invasion of other segments of colorectum by way
of the serosa or mesocolon (e.g. invasion of the sigmoid
colon by carcinoma of the cecum). Intramural extension
of the tumor from one subsite (segment) of the large
intestine into an adjacent subsite or into the ileum (e.g.
for a cecal carcinoma) or anal canal (e.g. for a rectal
carcinoma) does not affect the pT classification [25].
Evaluation of Regional Lymph Nodes
During pathologic examination of a resection speci-
men, all lymph nodes found are submitted for microscopic
examination. From any lymph node dissection, a total
of 12 regional nodes is often suggested as the minimum
acceptable number, but the actual number of lymph nodes
present in any given resection specimen may be limited by
anatomic variation, surgical technique or both. Regional
lymph nodes must be examined separately from lymph
nodes outside the anatomic site of the tumor. Metastases
in any lymph node in the regional nodal groups are classi-
fied as pN disease, whereas all other nodal metastases
are classified as pM1. The regional lymph node groups
of the anatomic subsites of the colorectum are shown in
table 3 [23]. Tumor of any amount in a regional lymph
node, whether carried there by afferent lymphatics or
arriving by direct invasion through the lymph node cap-
sule, is regarded as metastatic disease. No matter how
small the amount of metastatic tumor seen, the term
‘micrometastatic disease’ is not applied to a tumor identi-
fied by conventional light microscopy, but refers instead
to a tumor discovered on special studies (see below).
Microscopic examination of extramural adipose tissue
sometimes reveals discrete nodules of tumor that may
represent lymph nodes that have been replaced by a meta-
static tumor but cannot be identified as such with cer-
tainty. In order to eliminate arbitrary decisions by
different pathologists as to whether or not such nodules
are interpreted as nodal metastasis, the AJCC/UICC have
established the following guidelines. Any extramural
tumor nodule with the regional lymph node distribution
of the tumor that measures ?3 mm in diameter but lacks
Pathology Report in Colon Cancer
Table 3. Regional lymph nodes of the subsites of the colon and
rectum [23]
Cecum Anterior cecal, posterior cecal, ileocolic,
right colic
Ascending colon Ileocolic, right colic, middle colic
Hepatic flexure Middle colic, right colic
Transverse colon Middle colic
Splenic flexure Middle colic, left colic, inferior mesenteric
Descending colon Left colic, inferior mesenteric, sigmoid
Sigmoid colon Inferior mesenteric, superior rectal sigmoidal,
sigmoid mesenteric1
Rectosigmoid colon Perirectal 1, left colic, sigmoid mesenteric,
sigmoidal, inferior mesenteric, superior
rectal, middle rectal
Rectum Perirectal 1, sigmoid mesenteric, inferior
mesenteric, lateral sacral, presacral,
internal iliac, sacral promontory, superior
rectal, middle rectal, inferior rectal
1
Lymph nodes along the sigmoid arteries are considered pericolic
nodes, and their involvement is classified as pN1 or pN2 according
to the number involved. Perirectal lymph nodes include the mesorectal
(paraproctal), lateral sacral, presacral, sacral promontory (Gerota),
middle rectal (hemorrhoidal), and inferior rectal (hemorrhoidal)
nodes. Metastasis in the external iliac or common iliac nodes is classi-
fied as pM1 [25].
histologic evidence of residual lymph node tissue is classi-
fied as pN disease. However, tumor nodules measuring
p3 mm in diamter are classified in the pT3 category as
discontinuous extramural extension of tumor [25]. Mul-
tiple nodules ?3 mm in size are considered as metastasis
in a single lymph node for classification [23].
All TNM stage-related outcome data are derived from
studies in which the pathologic evaluation of the regional
lymph nodes has been performed by conventional histo-
logic staining of grossly identified lymph nodes. Most
nodal metastases in colorectal cancer are found in small
lymph nodes (=5 mm in diameter), the criteria for radio-
logic assessment of lymph node metastasis based on large
nodal size notwithstanding [70]. Therefore an aggressive
search for small nodes is essential. Unfortunately, due to
the lack of widely accepted pathology practice standards
for lymph node examination, there are many variations
in the basic pathologic techniques used for lymph node
harvesting and submission for microscopic analysis. Some
of these variations include: (1) the use of ‘clearing’ solu-
tions to improve visualization of small lymph nodes in
the pericolonic or perirectal fat; (2) the submission of
one half vs. both halves of each node for microscopic
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examination, and (3) the preparation of one vs. more
than one tissue level per paraffin block of submitted nodal
tissue [44, 71]. Thus, even by acceptable practices of
‘routine’ lymph node examination, the thoroughness of
the assessment varies.
The routine examination of lymph nodes for metastatic
disease does not include immunohistochemical or mo-
lecular methods such as antibodies to cytokeratins or
tumor-related antigens like carcinoembryonic antigen
(CEA) or reverse transcriptase-polymerase chain reaction
(RT-PCR) to identify RNA for tumor-related molecules.
These methods are costly and can be difficult to quality
control, but more importantly, the significance of the
findings generated from such analyses has yet to be deter-
mined. In one recent study of stage-II colorectal cancers
(n>26), more than 50% of cases showed evidence of
‘micrometastatic disease’ in histologically negative re-
gional lymph nodes when analyzed by RT-PCR for CEA
[72]. The 5-year survival rate was 50% for patients with
micrometastatic disease and 91% for patients without
micrometastasis. However, in a larger study (n>77) using
immunohistochemistry to identify micrometastasis (found
in 25% of cases), no difference in the 10-year survival
was observed among patients with and without micro-
metastasis [73]. At present, special studies are not indi-
cated as part of the routine examination and reporting
of regional lymph nodes in colorectal cancer specimens.
Definition of Distant Metastasis
As stated above, metastasis to any nonregional lymph
node or to any distant organ or tissue is categorized as
M1 disease. Peritoneal seeding of abdominal organs is
also considered M1 disease, as is positive peritoneal fluid
cytology. Isolated tumor cells found in the bone marrow
are classified as distant micrometastases but, like nodal
micrometastasis (see above), their significance is as yet
unproven [25].
Multiple tumor foci in the mucosa or submucosa of
adjacent bowel (‘satellite lesions’ or ‘skip metastasis’) are
not considered distant metastases. However, ‘satellite’ le-
sions must be distinguished from additional primary tu-
mors in which there is obvious evidence of origin from
an overlying adenoma.
Pathologic Staging of Residual Colorectal Carcinoma
By definition, the TNM categories describe the ana-
tomic extent of malignant tumors that have not been
previously treated, and the predictive value of the corre-
sponding TNM stage groupings is based solely on data
derived from outcome studies of such tumors following
74 Dig Dis 1999;17:67–79
complete surgical resection. A tumor that remains after
treatment (definitive or palliative) of any type (prior sur-
gery alone, radiation therapy alone, chemotherapy alone,
or any combined modality treatment) is codified by a
system known as the residual tumor or R classification
[23]: RX>presence of residual tumor cannot be assessed;
R0>no residual tumor; R1>microscopic residual tumor,
and R2>macroscopic residual tumor.
Use of the R classification would be applicable in any
of the following settings: (1) tumor remaining in a resec-
tion specimen after preoperative neoadjuvant nonsurgical
therapy (chemotherapy, radiation therapy or chemoradi-
ation therapy); (2) tumor remaining in a resection speci-
men following polypectomy of a malignant polyp (an
adenoma containing invasive carcinoma or a polypoid
carcinoma), or (3) tumor remaining in the patient after
curative resection (e.g. this might correspond to a prox-
imal, distal or radial resection margin (see below) that is
shown to be involved by tumor on pathologic examina-
tion).
The R classification encompasses both local and dis-
tant residual disease. However, the categories of the R
classification give no detailed information as to the ana-
tomic site or extent of residual disease. Therefore, it has
been proposed by the AJCC/UICC that the categories of
the TNM be used to describe residual disease using the
subscript ‘y’ as a modifier to indicate the posttreatment
status of the tumor (e.g. ypT2) [23]. For many therapies,
the classification of residual disease has been shown to
be a strong predictor of posttreatment outcome. In addi-
tion, the R/yTNM classification provides a standardized
framework for the collection of data needed to accurately
evaluate new therapies.
Pathologic Staging of Recurrent Colorectal Carcinoma
In contrast to residual disease, a tumor that is locally
recurrent after a documented disease-free interval follow-
ing definitive therapy should be classified according to
the TNM categories and modified with the prefix ‘r’ (e.g.
rpT1). By convention, the recurrent tumor is assigned
topographically to the proximal segment of the anasto-
mosis [23, 25].
Status of Surgical Resection Margins (Proximal, Distal,
Radial, and Mesenteric)
The pertinent margins of a colorectal cancer resection
specimen include the proximal, distal, and mesenteric
margin and, when appropriate, the radial margin. The
radial margin represents the retroperitoneal (colon) or
perineal (rectum) soft tissue margin closest to the deepest
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penetration of tumor. For all segments of the large intest-
ine that are either incompletely encased (ascending colon,
descending colon, upper rectum) or not encased (lower
rectum) by peritoneum, the radial margin is usually
created by blunt dissection of the retroperitoneal or peri-
neal (subperitoneal) soft tissues, respectively, at opera-
tion.
The radial margin has been demonstrated to be of
importance in relation to the risk of local recurrence after
surgical resection of the rectal carcinomas [74–77]. In
multivariate analyses, tumor involvement of the radial
margin has proven to be the single most critical factor
in predicting local recurrence in rectal cancer [76, 77].
For this reason, routine assessment of radial margins is
recommended in all colorectal cancers, and measurement
of the distance from the tumor to the radial margin,
representing the ‘surgical clearance’ around the tumor is
also suggested [40, 75]. The radial resection margin may
be considered ‘involved’ if the tumor is present 1 mm or
less from the nonperitonealized surface of the specimen.
For segments of the colon that are completely periton-
ealized (e.g. the transverse and sigmoid colon), the mesen-
teric resection margin may be a relevant ‘radial’ margin
since tumors may extend to this margin with or without
penetrating the serosal surface. The mesenteric resection
margin should be examined when the point of deepest
penetration of the tumor is on the mesenteric aspect of
the colon. For those tumors limited to an antimesenteric
peritonealized aspect of the bowel, the mesenteric margin
is not relevant.
Because of its association with local recurrence, in-
volvement of the radial or the mesenteric margin has
implications for adjuvant therapy. Whether the primary
tumor is classified as pT3 (without serosal penetration)
or pT4b (with serosal penetration), resection is considered
complete only if all surgical margins are negative, includ-
ing the radial margin. That is, whether or not the tumor
penetrates a serosal surface, resection is considered
complete if the resection margins are free of tumor. In
contrast, adjuvant therapy (e.g. local radiation) may
be appropriate regardless of the T category of the tumor
if a radial or mesenteric margin is involved by the
tumor.
Venous, Lymphatic, or Perineural Invasion by Tumor
Venous invasion by the tumor has been demonstrated
to have an independent adverse impact on outcome by
multivariate analysis in at least 10 different studies [26, 30,
31, 34–36, 53, 56, 63, 78] and by univariate analysis in
several additional studies [42, 79–81]. However, some
Pathology Report in Colon Cancer
studies identifying venous invasion as an adverse prog-
nostic factor on univariate analysis have failed to confirm
an independent effect on multivariate analysis [33, 82].
Similarly disparate results have been reported for lym-
phatic invasion as well [33, 35, 36, 44, 78, 80, 82–84]. Fur-
ther complicating the issue, several multivariate analyses
demonstrating vascular invasion to be a prognostically
significant factor have made no distinction between
lymphatic and venous vessels. In yet other studies, the
location of the vascular involvement (e.g. invasion of ex-
tramural veins) has been a strong determinate of the
associated prognostic significance [56, 57]. Overall, there-
fore, data from existing studies is difficult to amalgamate.
Nevertheless, the importance of venous and lymphatic
invasion by a tumor is strongly suggested and largely
confirmed by the literature.
It is likely that the disparities among existing studies on
vessel invasion are directly related to inherent problems of
pathologic analysis as discussed above (see Pathologic
Evaluation of Malignant Polyps). Even with interpreta-
tion of a large vessel (i.e. muscular vein) invasion, interob-
server variability may be substantial. Tumor infiltration of
the vessel wall and destruction of the vascular architecture
may make venous involvement difficult to recognize.
Special techniques such elastic tissue stains to highlight
venous walls may increase the accuracy of the pathologic
evaluation. However, these techniques are labor intensive,
time consuming, and expensive, and they are not routinely
performed. Additional limitations in the detection of ves-
sel invasion are related to specimen sampling. For ex-
ample, it has been shown that the reproducibility of
detection of extramural venous invasion increases from
59% with examination of 2 blocks of tissue from the
tumor periphery to 96% with examination of 5 blocks
of tissue [57]. At present, however, no widely accepted
standards or guidelines for the pathologic evaluation of
vessel invasion exist, and pathology sampling practices
may vary widely on both individual and institutional
levels. Complicating this issue is the impact of cost con-
tainment on surgical pathology practice which, in general,
has tended to minimalize the number of tissue blocks
submitted for resection specimens.
Tumor Border Configuration and Perineural Invasion
For colorectal cancer, the growth pattern of the tumor
at the advancing edge (tumor border) has been shown to
have prognostic significance that is independent of stage
and may predict liver metastasis. Specifically, an irregular,
infiltrating pattern of growth, as opposed to a pushing
border, has been demonstrated to be an adverse prog-
Dig Dis 1999;17:67–79 75
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Table 4. Diagnostic criteria for defiing infiltrating tumor border con-
figuration [45]
Naked eye examination of a microscopic slide of the tumor border
Inability to define limits of invasive border of tumor
and/or
Inability to resolve host tissue from malignant tissue
Microscopic examination of the tumor border
‘Streaming dissection’ of musculais propria (dissection of tumor
through the full thickness of the muscularis propria without
stromal response)
and/or
Dissection of mesenteric adipose tissue by small glands or irregular
clusters or cords of cells
and/or
Perineural invasion
nostic factor by several univariate [42, 56, 84, 85] and
multivariate analyses [32, 45, 46, 55, 87–89]. In some of
these studies, infiltrating tumor borders have been re-
ferred to as ‘focal dedifferentiation’ [85] and ‘tumor bud-
ding’ [88] and defined as microscopic clusters of undif-
ferentiated cancer cells just ahead of the invasive front
of the tumor. Whatever terms are used to describe the
tumor border configuration, pathologic assessment of this
feature in all transmurally invasive colorectal tumors has
been suggested [90].
In a study by Jass et al. [45], interobserver variability
among pathologists evaluating tumor border configura-
tion was found to be about 30% if no specific definitions
of infiltrating growth were provided. Concordance was
found to improve to 90% when the diagnostic criteria
shown in table 4 were employed, and use of these criteria
is, therefore, recommended [40]. Although perineural in-
vasion is one of the microscopic features included in the
definition of infiltrating growth (table 4), several studies
have shown by multivariate analysis that perineural inva-
sion itself is an independent indicator of poor prognosis
[18, 26, 30, 36, 44, 78, 91]. Therefore, perineural invasion
by a tumor may be reported separately [40, 90].
Host Lymphoid Response to Tumor
Lymphocytic infiltration of a tumor or peritumoral tis-
sue is indicative of a host immunologic response and has
been shown by multivariate analysis to be a favorable
prognostic factor [37, 45, 56, 87]. However, other studies
have either failed to confirm the prognostic significance of
a peritumoral lymphoid reaction [32, 89] or have de-
monstrated its significance only by univariate analysis
[42, 92–94]. The results of these studies are difficult to com-
76 Dig Dis 1999;17:67–79
Table 5. Summary of pathologic features of prognostic significance
in colorectal cancer
Pathologic stage
Local extent of tumor (T cateogory) including, if pertinent, depth
of penetration of extramural soft tissues for T3 tumors
Regional lymph node metastasis
Distant metastasis
Histologic grade
Small vessel (lymphatic or venular) invasion
Extramural venous invasion
Perineural invasion
Tumor border configuration
Host lymphoid response to tumor
Satus of surgical margins
Proximal and distal margins
Deep radial margin for all anatomic sites with a nonperitonealized
surface
Surgical clearance at deep radial margin, if applicable
pare since the histologic criteria for qualitative and quanti-
tative evaluation differ from study to study. Some of the
specific features that have been studied include perivascu-
lar lymphocytic cuffing in the muscularis propria, perivas-
cular lymphocytic cuffing in the pericolonic fat or
subserosa, lymphocytic infiltration at the tumor edge, and
a ‘Crohn’s-like’ lymphoid reaction (i.e. transmural peritu-
moral lymphoid follicle formation). In other reports, little
if any explanation of the criteria used for evaluation of this
parameter have been offered. However, because a host
lymphoid response appears to be a favorable prognostic
factor, it has been suggested that it be routinely evaluated
and documented in the pathology report [90].
Conclusion
The primary and most efficacious treatment for col-
orectal cancer is surgical resection, and the most powerful
tool for assessing prognosis following surgery is patho-
logic analysis of the resection specimen. Although the
tumor parameters that determine pathologic stage are
the strongest predictors of postoperative outcome in col-
orectal cancer, a number of additional pathologic features
have prognostic significance that is independent of stage.
A summary of prognostically significant pathologic fea-
tures is shown in table 5.
Currently, a large number of additional pathologic,
biochemical, and molecular genetic parameters that may
have prognostic value in colorectal cancer are currently
under investigation. Many will undoubtedly prove bio-
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logically important, either as prognostic factors, as fac-
tors that predict response to specific adjuvant or
neoadjuvant therapies, or both. Although our knowledge
about the prognostic significance of these variables is
expanding rapdily, it is not yet clear how this information
can be used effectively in patient care. As yet, there is no
readily available method for amalgamating all prog-
nostically important data into a single prognostic index
for the individual patient. Expansion of the TNM system
to include additional categories is impractical given the
mathematical model (i.e. a bin model system) on which
it is based. It is hoped that neural networks may provide
a means for simultaneous assessment of all prognostically
important data, but the application of neural networks
to this complicated prolem has only just begun. In the
meantime, an understanding of the biologic relevance of
all pertinent variables is essential for optimal, individual-
ized care of patients with colorectal cancer.

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