Colon and Rectum
Protocol
applies to all carcinomas of the colon and rectum. Carcinoid tumors, lymphomas,
sarcomas and tumors of the vermiform appendix are excluded
Procedures
• Excisional Biopsy, Polypectomy
• Local Excision (Transanal Disk Excision)
I. Incisional (endoscopic) biopsy back
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1. Patient identification
a. Name
b. Identification number
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date of procedure
4. Other clinical information
a. Relevant history
(1) previous colon adenoma(s)/carcinoma(s)
(2) familial adenomatous polyposis syndrome
(3) hereditary non-polyposis colon cancer syndrome
(4) familial hamartomatous polyposis syndrome
(5) inflammatory bowel disease
b. Relevant findings (e.g., colonoscopic and/or
imaging studies)
5. Clinical diagnosis (e.g., Crohn’s disease)
6. Procedure (e.g., colonoscopic biopsy)
7. Operative findings
8. Anatomic site(s) of specimen(s)
1. Specimen
a. Unfixed/fixed (specify fixative)
b. Number of pieces
c. Largest dimension of
each piece
d. Description of other
tissues (as appropriate)
2. Submit entire specimen for microscopic
evaluation
3. Special studies (specify) (e.g.,
histochemistry, immunohistochemistry, morphometry, DNA analysis [specify type],
cytogenetic analysis)
1. Tumor (Note A)
a. Histologic type (Note B)
b. Histologic grade (Note C)
c. Extent of invasion, as appropriate
2. Additional pathologic findings, if present
a. Colitis
b. Adenoma
c. Other(s)
3. Results/status of special studies (specify)
4. Comments
a. Correlation with
other specimens, as appropriate
b. Correlation with
clinical information, as appropriate
II. Excisional biopsy, polypectomy back
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1. Patient identification
a. Name
b. Identification number
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date of procedure
4. Other clinical information
a. Relevant history
(1) previous colon adenoma(s)/carcinoma(s)
(2) familial
adenomatous polyposis syndrome
(3) hereditary
non-polyposis colon cancer syndrome
(4) familial
hamartomatous polyposis syndrome
(5) inflammatory bowel
disease
b. Clinical diagnosis
c. Procedure (e.g., polypectomy)
d. Operative findings
e. Anatomic site(s) of specimen(s)
1. Specimen
a. Tissue(s) included
b. Unfixed/fixed (specify fixative)
c. Number of pieces
d. Dimensions
e. Orientation (if indicated by surgeon)
f. Descriptive features (e.g., color,
consistency)
2. Polyp
a. Configuration (e.g., pedunculated, sessile)
b. Size (three dimensions)
c. If pedunculated, length of stalk (margin of
stalk may be inked)
d. Dimension of carcinoma (diameter), if
possible
e. Tissue(s) submitted for microscopic
evaluation
f. Transverse (coronal) section(s) through
polyp, include:
(1) polyp apex and stalk or base in same section,
if possible
(2) carcinoma, point of deepest invasion
(3) longitudinal section of polyp stalk (as
appropriate)
3. Special studies (specify) (e.g.,
histochemistry, immunohistochemistry, morphometry, DNA analysis [specify type],
cytogenetic analysis)
1. Polyp
a. Histologic type
2. Tumor (Carcinoma
within polyp)
a. Histologic type (Note B)
b. Histologic grade (Notes C and D)
c. Extent of invasion (Note D):
d. Blood/lymphatic
vessel invasion (Note D)
e. Distance of carcinoma
from margin (Note D)
3. Results/status of
special studies (specify)
4. Comments
a. Correlation with
other specimens, as appropriate
b. Correlation with
clinical information, as appropriate
III. Local Excision (transanal disc excision) back
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1. Patient identification
a. Name
b. Identification number
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date of procedure
4. Other clinical information
a. Relevant history
(1) previous colon adenoma(s)/carcinoma(s)
(2) familial adenomatous polyposis syndrome
(3) hereditary non-polyposis colon cancer syndrome
(4) familial hamartomatous polyposis syndrome
(5) inflammatory bowel disease
b. Relevant findings (e.g., colonoscopic and/or
imaging studies)
c. Clinical diagnosis
d. Procedure (e.g., transanal resection)
e. Operative findings
f. Anatomic site(s) of specimen(s)
1. Specimen
a. Unfixed/fixed (specify fixative)
b. Number of pieces
c. Dimensions
d. Orientation of specimen (if indicated by
surgeon)
e. Descriptive characteristics (e.g., color,
consistency)
f. Layers of colon/rectum present (if grossly
discernible)
g. Results of intraoperative consultation
2. Tumor (Note A)
a. Configuration (Note E)
b. Dimensions (three dimensions)
c. Distance of tumor edge from closest margin
d. Estimated depth of invasion
e. Lesions in noncancerous colon/rectum (e.g.,
colitis, polyps)
3. Additional pathologic findings, if present
4. Tissue(s) submitted for microscopic
evaluation
a. Carcinoma, including:
(1) points of deepest penetration
(2) interface with
adjacent colon
(3) margin closest to
tumor edge
b. Frozen section tissue fragment(s) (unless
saved for special studies)
5. Special studies (specify) (e.g.,
histochemistry, immunohistochemistry, morphometry, DNA analysis [specify type],
cytogenetic analysis)
1. Tumor
a. Histologic type (Note B)
b. Histologic grade (Note C)
c. Extent of invasion (Note F)
d. Blood/lymphatic vessel invasion (Note
G)
e. Perineural invasion (Note G)
f. Extramural venous invasion (Note
H)
g. Peritumoral lymphocytic response (Note
I)
h. Pattern of growth at tumor periphery (Note J)
(1) infiltrating border
(2) pushing border
2. Margins
a. Distance of carcinoma from closest mucosal
margin and/or deep margin
3. Additional pathologic findings, if present
a. Colitis
b. Dysplasia
c. Adenomas
d. Hyperplastic polyps
e. Other(s)
4. Results/status of special studies (specify)
5. Comments
a. Correlation with intraoperative consultation,
as appropriate
b. Correlation with other specimens, as
appropriate
c. Correlation with clinical information, as
appropriate
IV.
Segmental resection back Top Main Page
1. Patient identification
a. Name
b. Identification number
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date of procedure
4. Other clinical information
a. Relevant history
(1) previous colon adenoma(s)/carcinoma(s)
(2) familial adenomatous polyposis syndrome
(3) hereditary non-polyposis colon cancer syndrome
(4) familial hamartomatous polyposis syndrome
(5) inflammatory bowel disease
b. Relevant findings (e.g., colonoscopic and/or
imaging studies)
c. Clinical diagnosis
d. Procedure (e.g., right colectomy, transverse
colectomy, left colectomy, sigmoidectomy, abdomno-peroneal resection)
e. Operative findings
f. Anatomic site(s) of
specimen(s) (e.g., cecum, right, transverse, descending, sigmoid colon, or
rectum)
1. Specimen
a. Organ(s)/tissue(s) included
b. Unfixed/fixed (specify fixative)
c. Number of pieces
d. Dimensions
e. Orientation of specimen (if indicated by
surgeon)
f. Results of intraoperative consultation
2. Tumor
a. Location (Note A)
b. Configuration (Note E)
c. Dimensions (three dimensions)
d. Descriptive characteristics (e.g., color,
consistency)
e. Ulceration/perforation
f. Distance from margins (Note K)
(1) proximal
(2) distal
(3) radial (soft tissue margin or serosa closest
to deepest tumor penetration)
g. Estimated depth of invasion (Note
F)
3. Lesions in noncancerous colon/rectum (e.g.,
colitis, other polyps)
4. Regional lymph nodes (Note F)
5. Metastasis to other organ(s) or structure(s) (Note F)
6. Colon/rectum uninvolved by tumor
7. Other tissue(s)/organ(s)
8. Tissues submitted for microscopic evaluation
a. Carcinoma, including:
(1) points of deepest penetration
(2) interface with adjacent colon/rectum
(3) visceral serosa overlying tumor
b. Margins (Note K)
(1) proximal
(2) distal
(3) radial (soft tissue margin closest to deepest
tumor penetration)
c. All lymph nodes (Note F)
d. Other lesions (e.g., polyps/colitis)
e. Frozen section tissue fragment(s) (unless
saved for special studies)
9. Special studies (specify) (e.g.,
histochemistry, immunohistochemistry, morphometry, DNA analysis [specify type],
cytogenetic analysis)
1. Tumor
a. Histologic type (Note B)
b. Histologic grade (Note C)
c. Extent of invasion (Note F)
d. Blood/lymphatic vessel invasion (Note
G)
e. Perineural invasion (Note G)
f. Extramural venous invasion (Note
H)
g. Peritumoral lymphocytic response (Note
I)
h. Pattern of growth at tumor periphery (Note J)
(1) infiltrating border
(2) pushing border
i. Associated pericolorectal abscess formation
(if present)
j. Associated pneumatosis intestinalis (if
present)
2. Margins (Note K)
a. Proximal
b. Distal
c. Radial (specify distance of carcinoma from
closest radial margin)
3. Regional lymph nodes (Note F):
a. Number
b. Number involved by tumor
4. Additional pathologic findings, if present
a. Inflammatory bowel disease
b. Dysplasia
c. Adenomas
d. Other types of polyps
5. Distant metastasis, specify site (Note
F)
6. Other tissue(s)/organ(s)
7. Results/status of special studies (specify)
8. Comments
a. Correlation with intraoperative consultation,
as appropriate
b. Correlation with other specimens, as
appropriate
c. Correlation with clinical information, as
appropriate
EXPLANATORY NOTES
A. Anatomic Sites back
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The protocol
applies to all carcinomas arising in the colon and rectum.(1) It excludes
carcinomas of the vermiform appendix.
The colon is
divided into four parts: the right (ascending colon), the middle (transverse)
colon, the left (descending) colon, and the sigmoid colon. The right colon is
subdivided into the cecum (peritoneally located and measuring about 6 x 9 cm)
and the ascending colon (located retroperitoneally and measuring 15 to 20 cm
long). The descending colon, also located retroperitoneally, is 10 to 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.(1)
Tumors located
at the border between 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. 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 extends 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.(2) A
tumor is classified as rectosigmoid when differentiation between rectum and
sigmoid according to the above guidelines is not possible.(3)
B. Histologic Types back
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For consistency
in reporting, the histologic classification proposed by the World Health
Organization (WHO) is recommended and is shown below.(4)
However, this protocol does not preclude the use of other systems of
classification or histologic types.
• Adenocarcinoma
in situ/severe dysplasia*
• Adenocarcinoma
• [Medullary
carcinoma]**
• Mucinous
(colloid) adenocarcinoma (>50% mucinous)***
• Signet-ring
cell carcinoma (>50% signet-ring cells)†
• Squamous cell
(epidermoid) carcinoma
• Adenosquamous
carcinoma
• Small-cell
(oat cell) carcinoma†
•
Undifferentiated carcinoma†
• Other
(specify)‡
* In order to
avoid confusion with the term "carcinoma in situ" as it applies to
pTis in the TNM staging (see Note F below), it has been recommended that the
term "intraepithelial carcinoma" be used to refer to histologically
malignant epithelium that does not penetrate the basement membrane (i.e., shows
no evidence of stromal [lamina propria] invasion).(5,6)
** Medullary
carcinoma has been added to the revised WHO histological classification that
will be published in 2000. Medullary carcinoma is a histologic type that is
strongly associated with a high degree of microsatellite instability (MSI-H)
indicative of loss of normal DNA repair gene function.(6-8)
With loss of function of any of the genes involved in the repair of
mitosis-associated mistakes in DNA synthesis (i.e., replication errors),
mutations in daughter cells are rapidly accumulated. Ultimately, tumors with
defective DNA repair acquire inactivating mutations of genes necessary for
complex biologic activities such as metastasis. For this reason, tumors with
MSI-H, such as most (if not all) medullary carcinomas, have a favorable
prognosis compared to microsatellite stable (MSS) tumors or tumors with low
levels of microsatellite instability (MSI-L). Medullary carcinoma may occur
either sporadically(7) or
in association with the hereditary nonpolyposis colon cancer syndrome (HNPCC).(8) This tumor type is
characterized by uniform polygonal tumor cells that exhibit solid growth in
nested, organoid, or trabecular patterns and that only focally produce small
amounts of mucin. In addition, medullary carcinomas are typically infiltrated
by lymphocytes (tumor infiltrating lymphocytes) and have no immunohistochemical
evidence of neuroendocrine differentiation.
*** In most
previous studies on prognostic factors in colorectal cancer, the impact of
genetic status (i.e., loss of DNA repair gene function with microsatellite
instability) on the relationship between histologic type and outcome has not
been considered. This shortfall is particularly relevant to mucinous carcinoma,
a histologic type that is common among tumors with MSI-H. Overall, most
mucinous carcinomas are MSS. Thus, it is not surprising that, the prognostic
significance of mucinous carcinoma has proven controversial.(6,9) A few studies,
largely limited to univariate analyses, have indicated that mucinous
adenocarcinoma may be an adverse prognostic factor. Alternatively, mucinous
carcinoma has been linked with adverse outcome only when occurring in specific
anatomic regions of the bowel (e.g., the rectosigmoid) or in a specific subsets
of patients (i.e., those less than 45 years of age). In yet other studies,
mucinous carcinoma has been linked to adverse outcome only when mucinous and
signet-ring cell carcinomas have been grouped together and compared to typical
adenocarcinoma. Data of this type may merely reflect the aggressive biologic
behavior of most signet-ring cell tumors. Only one multivariate analysis has
shown mucinous carcinoma to be a stage-independent predictor of adverse
outcome, but the study was limited to tumors presenting with large bowel
obstruction, which itself is an adverse prognostic factor (for review see ref.
9).
† By convention,
signet-ring cell carcinomas, small cell carcinomas and undifferentiated
(histologic type) carcinomas are high grade (see below). The only histologic
types of colorectal carcinoma that have been shown to have adverse prognostic
significance independent of stage are signet-ring cell carcinoma and small-cell
carcinoma.(9) Nevertheless, signet ring cell carcinoma may occur in HNPCC in
association with MSI-H.(10) Thus, in cases of MSI-H signet ring cell carcinoma,
it may be expected that the prognostic significance would be determined by the
molecular pathogenesis and would be favorable.
‡The term
"carcinoma, NOS" (not otherwise specified) is not part of the WHO
classification.
C. Histologic Grade back
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A number of
grading systems have been suggested in the literature, but a single widely
accepted and uniformly employed standard for grading is lacking. Among the
suggested grading schemes, the number of grades as well as the criteria for
distinguishing among different grades vary markedly. In some systems, grades
are defined on the basis of a single microscopic feature, such as the degree of
gland formation, and in other systems, a large number of features are included
in the evaluation. Irrespective of the complexity of the criteria, however,
most systems stratify tumors into three or four grades as follows:
Grade 1 Well differentiated
Grade 2 Moderately differentiated
Grade 3 Poorly differentiated
Grade 4 Undifferentiated
Variation in the
appearance of individual histologic features may vary widely enough to make
implementation of the even the simplest grading systems problematic and,
ultimately, subjective. Thus, a significant degree of interobserver variability
in the grading of colorectal cancer has been shown to exist.(9,11) Nevertheless,
despite this variability, histologic grade has repeatedly been shown by
multivariate analysis to be a stage-independent prognostic factor.(9,12,13) In specific,
it has been demonstrated that high tumor grade is an adverse prognostic factor.
It is noteworthy that in the vast majority of studies documenting the
prognostic power of tumor grade,(9)
the number of grades has been collapsed to produce a two-tiered stratification
for data analysis as follows:
Low Grade Well differentiated and moderately
differentiated
High Grade Poorly differentiated and
undifferentiated
In general practice, a two-tiered grading
systems would also be expected to greatly reduce interobserver variability,
since the widest variations in grading concern the stratification of low grade
tumors into well- or moderately-differentiated categories. Pathologic
identification of poorly differentiated or undifferentiated tumors is more
consistent, and interobserver variability in diagnosing high-grade carcinoma is
relatively small. Therefore, in light of its proven prognostic value, relative
simplicity, and reproducibility, a two-tiered grading system for colorectal
carcinoma (i.e., low grade and high grade) is recommended.(6) The grading should
be based on gland formation alone as follows(6):
Low grade = >
50% gland formation
High grade =
< 50% gland formation.
D. Carcinoma in an Adenomatous Polyp back
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Colorectal
adenomas containing invasive adenocarcinoma that extends through the muscularis
mucosae into the submucosa have been defined as "malignant polyps."
These polyps constitute a form of early (i.e., curable) colorectal carcinoma.
The definition of malignant polyps excludes adenomas with intraepithelial
carcinoma or intramucosal carcinoma (invasive carcinoma limited to the lamina
propria or invading no deeper than the muscularis mucosae) because these polyps
possess no biological potential for metastasis (see Tis in Note F below). The term "malignant
polyp" encompasses both polypoid carcinomas in which the entire polyp head
is replaced by carcinoma and adenomas with focal malignancy.
Malignant polyps
removed by endoscopic polypectomy require evaluation of histologic parameters
that have been determined to be significant prognostic factors related to the
risk of adverse outcome (i.e., lymph node metastasis or local recurrence from
residual malignancy) following polypectomy.(9,
14-30) Pathologic features that have been shown to have
independent prognostic significance and are crucial for evaluating risk and
determining the possible need for further surgical treatment (e.g., segmental
colectomy) include:
• histologic
grade of the carcinoma
• extent (level)
of invasion of the carcinoma within the polyp
• status of the
resection margin
•
lymphatic/venous vessel involvement
Specifically, an
increased risk of adverse outcome has been shown to be associated with:
• grade 3
(poorly differentiated) carcinoma
• tumor at or
less than 1 mm from the resection margin
• presence of
lymphatic/venous vessel involvement
E.
Tumor Configuration back Top Main Page
Configurations
include exophytic (fungating), endophytic (ulcerative), and diffusely
infiltrative (linitis plastica), or annular, but overlap among these types is
common. Exophytic is divided into pedunculated and sessile. Overall, gross
tumor configuration has no independent influence on prognosis.(6,9) The uncommon
linitis plastica type represents a possible exception. It has an unfavorable
prognosis, but its association with adverse outcome is probably related to the
underlying histologic type of tumor (signet ring cell carcinoma) rather than
the macroscopic configuration itself.
F. TNM and Stage Groupings back Top Main Page
Surgical
resection remains the most effective therapy for colorectal carcinoma, and the
best estimation of prognosis is related to the pathologic findings on the
resection specimen. The anatomic extent of disease is by far the most important
prognostic factor in colorectal cancer.(12)
The protocol
recommends the TNM Staging System of the American Joint Committee on Cancer
(AJCC) and the International Union Against Cancer (UICC)(1,31) but does not
preclude the use of other staging systems.
The designation
"T" refers to the first resection of a primary tumor. The symbol
"pT" refers to the pathologic classification of the TNM, as opposed
to the clinical classification. Pathologic classification is based on gross and
microscopic examination. pT entails a resection of the primary tumor or biopsy
adequate to evaluate the highest pT category; pN entails removal of nodes
adequate to validate lymph node metastasis; and pM implies microscopic
examination of distant lesions. Clinical classification (cTNM) is usually
carried out by the referring physician before treatment during initial
evaluation of the patient or when pathologic classification is not possible and
is typically based on information obtained by physical examination, serologic
analyses, imaging studies, etc.(1)
Tumor (T)
TX Primary tumor cannot be assessed
TO No evidence of primary tumor
Tis Carcinoma in situ - intraepithelial or
invasion of the lamina propria or muscularis mucosae*
T1 Tumor invades the submucosa
T2 Tumor invades the muscularis propria
T3 Tumor invades through the muscularis
propria into the subserosa or into the nonperitonealized pericolic or
perirectal tissues**
T3a minimal invasion: <1 mm beyond the
border of the muscularis propria
T3b slight invasion: 1-5 mm beyond the border
of the muscularis propria
T3c moderate invasion: >5-15 mm beyond the
border of the muscularis propria
T3d extensive invasion: >15 mm beyond the
border of the muscularis propria
T4 Tumor directly invades other organs
or structures† (T4a) or perforates the
visceral peritoneum‡ (T4b)
*For colorectal carcinomas, "carcinoma in situ" (Tis) as a staging term
includes cancer cells confined within the glandular basement membrane
(intraepithelial carcinoma) or invasive into the mucosal lamina propria, up to
but not through the muscularis mucosae (intramucosal carcinoma). This may be
confusing because, in all other organ systems, the term "carcinoma in
situ" is used to refer exclusively to malignancy that does not invade the
underlying stroma. Therefore, for colorectal cancer, the terms
"intraepithelial carcinoma" and "intramucosal carcinoma"
are recommended as descriptive terms to subclassify pTis and to clarify the
status of the tumor.(5,6)
Tumor extension through the muscularis mucosae into the submucosa is classified
as T1. Some pathologists classify intraepithelial carcinoma as severe or high-grade dysplasia,
especially in cases of inflammatory bowel disease.
**The extent of
perimuscular invasion has been reported to influence prognosis, regardless of
whether regional lymph node metastasis is present. Thus, an optional expansion
pT3 has been proposed.(3)
Extramural extension >5mm has been shown to be the critical subdivision
associated with adverse outcome in most studies. Thus, a simpler subdivision,
based on extension of <5mm vs. >5mm (i.e., pT3a,b vs. pT3c,d), may be
justified. (3) Extension of the
tumor within lymphatics or veins does not count as local spread of tumor as
defined by the T classification.(3)
† Direct
invasion of other organs or structures includes invasion of other segments of
colorectum by way of the serosa or mesocolon for example, invasion of the
sigmoid colon by carcinoma of the cecum. Intramural extension of 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.(3)
‡ Perforation of
carcinoma through a peritonealized surface of the colon is classified as T4b. (3) Subdivision of T4
into T4a and b is justified because a number of large studies that have
evaluated serosal penetration as an independent prognostic variable have
demonstrated by multivariate analysis that it has a strong negative impact on
prognosis.(32-35) In specific, it
has been shown that the frequency of distant metastasis is higher in cases with
perforation of the visceral peritoneum compared to cases with direct invasion
of adjacent organs or structures without perforation of the visceral peritoneum
(occurring in about 50% and 30% of cases, respectively).(3) Furthermore, the
median survival time following surgical resection for cure has been shown to be
shorter for patients with pT4b tumors compared to those with pT4a tumors (with
or without distant metastasis) as follows:(3)
pT4a,M1 12% 22.7
pT4b,M1 0% 15.5
A study by
Shepherd et al.(34) has suggested that
the prognostic power of local peritoneal involvement in curative resections may
supersede that of either local extent of tumor (T category) or regional lymph
node status (N category). However, serosal penetration is often difficult to
assess histopathologically and may be underdiagnosed. Documentation of
peritoneal involvement by tumor demands meticulous pathologic analysis and may
require extensive sampling and/or serial sectioning and can be missed on
routine histopathologic examination. It has been shown that cytologic
examination of serosal scrapings reveals malignant cells in as many as 26% of
tumor specimens categorized as pT3 by histologic examination alone.(34,36) In addition, the
histopathologic findings associated with peritoneal penetration are
heterogeneous and standard guidelines for their diagnostic interpretation are
lacking. Therefore, interobserver variability in the diagnosis of peritoneal
penetration may be substantial, and since most pathologists tend to err on the
side of conservative interpretation, underdiagnosis is likely for this reason
as well.
Shepherd et al.(34) analyzed the
spectrum of microscopic features that may be seen with local peritoneal
involvement by tumor, and defined three types of local peritoneal involvement
as follows:
1) a mesothelial
inflammatory and/or hyperplastic reaction with 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;
3) free tumor
cells on the serosal surface (in the peritoneum) with underlying ulceration of
the visceral peritoneum.
All three types
of local peritoneal involvement were associated with decreased survival,
whereas tumor well clear of the serosal had no independent adverse effect on
prognosis. Therefore, it is recommended that in that diagnosis of T4b encompass
the three types of serosal involvement detailed above.(6)
Free perforation
of a colorectal carcinoma into the peritoneal cavity is always classified as
T4.
NX Regional lymph nodes cannot be assessed
NO No regional lymph node metastasis
N1 Metastasis in 1 to 3 lymph nodes
N2 Metastasis in 4 or more lymph nodes**,***
*The regional lymph nodes for the anatomical
subsites of the large intestine are as
follows:
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 mesenteric
Rectosigmoid - perirectal, left colic, sigmoid
mesenteric, sigmoidal, inferiormesenteric, superiorrectal, middle rectal
Rectum - perirectal, sigmoid mesenteric, inferior mesenteric,
lateral sacral, presacral, internal iliac, sacral promontory, superior rectal,
middle rectal, inferior rectal
**Nodes along
the sigmoid arteries are considered pericolic nodes, and their involvement is
classified as N1 or N2 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
classified as distant metastasis.(3)
Important notes on Lymph Nodes:
Submission of
lymph nodes for microscopic examination: All grossly negative or equivocal
lymph nodes are to be submitted entirely.(6)
Grossly positive lymph nodes may be partially submitted for microscopic
confirmation of metastasis.
It has been
shown that 12 to 15 negative lymph nodes predict for regional node negativity.
Therefore, if fewer than 12 nodes are found, additional techniques (i.e.,
visual enhancement techniques) should be considered.(6)
If fewer than 12 nodes are found after the use of visual enhancement
techniques, this should be communicated in the pathology report. The pathology
report should clearly state the total number of lymph nodes examined and the
total number involved by metastases. Data are insufficient to recommend routine
use of tissue levels or special/ancillary techniques.(6)
Non-regional
lymph nodes: For microscopic examination of lymph nodes in large resection
specimens, lymph nodes must be designated as regional vs. non-regional,
according to the anatomic location of the tumor. Metastasis to non-regional
lymph nodes is classified as distant metastasis and designated as M1 (see
below).
Lymph nodes
replaced by tumor: A tumor nodule >3 mm in diameter in the perirectal or
pericolonic adipose tissue without histologic evidence of residual lymph node
in the nodule is classified as regional perirectal/pericolonic node metastasis.
However, a tumor nodule <3 mm in diameter is classified in the T category as
discontinuous extension (i.e., T3).(1,3)
Multiple metastatic foci seen microscopically only in the pericolonic fat
should be considered as metastasis in a single lymph node for classification.(1)
Micrometastasis:
Routine assessment of regional lymph node metastasis is limited to the use of
conventional pathologic techniques (gross assessment and histologic
examination). A solitary focus of tumor in a single lymph node that is
visualized by routine histologic examination and measures <2.0 mm may be
defined as a "micrometastasis".(6)
The biologic significance of micrometastatic disease (either a single focus in
a single node, multiple foci within a single node, or micrometastatic
involvement of multiple nodes) as yet is unproven. Pending definitive studies,
it is recommended that micrometastases be classified as pN1 but reported with a
note explaining that the biologic significance is unknown. The number of lymph
nodes involved by micrometastases should be clearly stated.(6)
The biologic
significance of metastasis detected only by special studies (e.g.,
immunohistochemical staining or molecular analysis) is also unproven at
present. It is recommended that metastasis diagnosed on special studies alone
also be reported with a note explaining the unknown significance of the
findings, but, in contrast to histologically identified micrometastases, be
classified as pN0.(6) Currently, the data are insufficient to recommend either
the routine examination of multiple tissue levels of paraffin blocks or the use
of special/ancillary techniques such as immunohistochemistry for epithelial
and/or tumor-associated antigens (e.g., cytokeratin, carcinoembryonic antigen,
etc.) or polymerase chain reaction (PCR) techniques to identify tumor RNA/DNA.(6)
Distant Metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis*
*Seeding of abdominal organs is considered
M1.
Stage
Groupings (TNM)
Tumor remaining
in a patient after therapy with curative intent (e.g., surgical resection) is
categorized by a system known as R classification, shown below.(1,6,12)
For example, this classification may be used by the surgeon to indicate the
known or assumed status of the completeness of the surgical resection. For the
pathologist, the R classification is relevant only to the margins of surgical
resection specimens. That is, tumor involving the proximal, distal or radial
(circumferential) resection margin [see below Note K below] on pathologic
examination may be assumed to correspond to residual tumor in patient and classified
as to whether the involvement is macroscopic or microscopic.(6)
R0 No residual tumor
R1 Microscopic residual tumor
R2 Macroscopic residual tumor.
Tumor remaining
in a resection specimen following previous (neoadjuvant) treatment of any type
(radiation therapy alone, chemotherapy therapy alone, or any combined modality
treatment) is codified by the TNM using a prescript "y" to indicate
the post-treatment status of the tumor (e.g., ypT1).(1,6)
For many therapies, the classification of residual disease has been shown to be
a strong predictor of postoperative outcome. In addition, the ypTNM
classification provides a standardized framework for the collection of data
needed to accurately evaluate new neoadjuvant therapies.
Tumor that is
locally recurrent after a documented disease-free interval following surgical
resection is classified according to the TNM categories but modified with the
prefix "r" (eg, rpT1). By convention, the recurrent tumor is
topographically assigned to the proximal segment of the anastomosis unless that
segment is small intestine.(1,3)
G. Lymphatic (Thin-Walled) Vessel and
Perineural Invasion back Top Main Page
In several
studies, both lymphatic invasion and perineural invasion have been shown by
multivariate analysis to be independent indicators of poor prognosis.(13,32,30,37,38) The
prognostic significance, if any, of the anatomic location of these structures
is not defined. Furthermore, it is not always possible to distinguish lymphatic
vessels from post-capillary venules since both are small, thin-walled
structures. Thus, the presence or absence of tumor invasion of small,
thin-walled vessels should be reported in all cases and its anatomic location
within the colonic wall noted.(6)
Tumor in veins
or lymphatics does not affect the pT classification. The L and V classifications
can be used to record such spread as follows:
Lymphatic
Vessel Invasion (L)
LX Lymphatic vessel invasion cannot be
assessed
L0 No lymphatic vessel invasion
L1 Lymphatic vessel invasion
Venous
Invasion (V)
VX Venous invasion cannot be assessed
V0 No venous invasion
V1 Venous invasion
H. Venous Invasion back
Top Main
Page
Extramural
venous invasion has been demonstrated by multivariate analysis to be an
independent adverse prognostic factor.(13,32,38-41)
Invasion of extramural veins, in particular, has been shown to be an
independent indicator of unfavorable outcome and increased risk of occurrence
of hepatic metastasis.(40,41)
It has been shown that the submission of 5 or more blocks of tumor
significantly enhances the likelihood of finding extramural venous invasion
when it exists and reduces false negativity due to sampling error.(42)
The significance
of intramural venous invasion is less clear, because data specific to this
issue are lacking. Nevertheless, it is recommended that the presence or absence
of venous invasion and its anatomic location should be reported in all cases.(6)
The V
classification as shown above may be used to record venous invasion.
I. Lymphoctyic Response to Tumor back
Top Main
Page
A conspicuous
lymphoid reaction at the leading edge of invasive tumor or the presence of
lymphoid aggregates in the surrounding tissues (muscularis external and
pericolonic or perirectal fat) have both been shown to be independent favorable
prognostic factors.(11,41,43-45)
Intratumoral lymphocytic infiltrates are closely associated with microsatellite
instability and medullary architecture (see above) and should be distinguished
from peritumoral infiltrates. Only moderate and high density intratumoral
lymphocytes (approximately 4 or more per high-power field) should be considered
significant.(6) Reporting of host
lymphoid response is optional. If reported, distinction should be made between
peritumoral and intratumoral lymphoid infiltrates.
J.
Tumor Periphery: Growth Pattern back Top Main Page
The growth
pattern at the advancing edge of the tumor has been shown to have prognostic
significance independent of stage and may predict liver metastasis.(46-52) Specifically, an
infiltrating pattern of growth at the tumor border as opposed to a pushing
border is an adverse prognostic factor.
Infiltrating
borders have been defined as follows:(47)
• Inability to
define limits of invasive border of tumor [and/or]
• Inability to
resolve host tissue from malignant tissue
•
"Streaming dissection" of muscularis 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
Irregular growth
at the tumor periphery has also been referred to as "focal
dedifferentiation" and "tumor budding" and defined as microscopic
clusters of undifferentiated cancer cells just ahead of the invasive front of
the tumor.
It may be
helpful to mark the margin(s) closest to the tumor with ink. Margins marked by
ink should be designated in the macroscopic description. Margins include the
proximal, distal, and radial margins. The radial margin represents the
adventitial soft tissue margin closest to the deepest penetration of tumor. For
all segments of the large intestine that are either incompletely encased
(ascending colon, descending colon, sigmoid colon, upper rectum) or not encased
(lower rectum) by peritoneum, the radial margin is created by blunt dissection
of the retroperitoneal or subperitoneal aspect, respectively, at operation.
The radial
margin has been demonstrated to be of importance in relation to risk of local
recurrence after surgical resection of the rectal carcinomas.(53-55) In fact,
multivariate analysis has suggested that tumor involvement of the radial margin
is the most critical factor in predicting local recurrence in rectal cancer.(53-55) For this reason,
routine assessment of the radial margin is suggested in all colorectal cancers,
and the measurement of the distance from the tumor to the radial margin
(representing the "surgical clearance" around the tumor) is
suggested.(56) For segments of the
colon that are completely encased by a peritonealized (serosal) surface (eg,
transverse colon), the only radial margin is the mesenteric resection margin,
and it is relevant when the point of deepest penetration of the tumor is on the
mesenteric aspect of the colon and extends to this margin with or without penetrating
the serosal surface. For those tumors limited to an antimesenteric
peritonealized aspect of the bowel, the radial margin is not relevant.
Because of its
association with local recurrence, involvement of the radial margin has
implications for adjuvant therapy. Whether the primary tumor is T3 (without
serosal penetration) or T4b (with serosal penetration), resection is considered
complete only if all surgical margins are negative including the radial margin.
That is, whether or not the tumor penetrates a serosal surface, resection is
considered complete if the resection margins (proximal, distal and radial) do
not contain tumor. If a radial margin is involved by tumor, adjuvant therapy
(eg, local radiation) may be appropriate.
Sections to evaluate the proximal and distal
resections margins can be obtained in two orientations: 1) en face sections
parallel to the margin or 2) longitudinal sections perpendicular to the margin.
Depending on the closeness of the tumor to the margin, select the
orientation(s) that best demonstrate(s) the status of the margin. The distance
from the tumor edge to the closest resection margin(s) should be measured. In
cases of carcinoma arising in a background of inflammatory bowel disease,
proximal and distal resection margins should be evaluated for dysplasia and
active inflammation.
1. Fleming ID, Cooper JS, Henson DE, et
al. eds. AJCC Manual for Staging of
Cancer. 5th ed. Philadelphia, Pa: Lippincott Raven; 1997.
2. Fielding LP, Arsenault PA, Chapuis PH,
et al. Clinicopathological staging for colorectal cancer: An International
Documentation System (IDS) and an International Comprehensive Terminology
(ICAT). J Gastroenterol Hepatol.
1991;6:325-344.
3. Hermanek P, Henson DE, Hutter RVP,
Sobin LH. TNM Supplement. New York,
NY: Springer-Verlag NY Inc; 1993.
4. Jass JR, Sobin LH. Histological Typing of Intestinal Tumours: World Health Organization.
2nd ed. New York, NY: Springer-Verlag NY Inc; 1989.
5. Compton CC, Fenoglio-Preiser CM,
Pettigrew N, Fielding LP. American Joint Committee on Cancer Prognostic Factors
Consensus Conference: Colorectal Working Group. Cancer. 2000 Apr 1;88(7):1739-57.
6. Compton CC, Fielding LP, Burgart LJ, et
al. Prognostic Factors in Colorectal Cancer: College of American Pathologists
Consensus Statement 1999. Arch Pathol Lab
Med. 2000 Jul;124(7):979-94.
7. Kim H, Jen J, Vogelstein B, Hamilton
SR. Clinical and pathological characteristics of sporadic colorectal carcinomas
with DNA replication errors in microsatellite sequences. Am J Pathol. 1994;145:148-156.
8. Jass JR, Smyrk TC, Stewart SM, Lane MR,
Lanspa SJ, Lynch HT. Pathology of Hereditary Non-polyposis Colon Cancer. Anticancer Research. 1994;14:1631-1634.
9. Compton CC. Pathology report in colon
cancer: What is prognostically important? Dig
Dis. 1999;17:67-79.
10. Symrk TC. Colon cancer connections.
Cancer syndrome meets molecular biology meets histopathology. Am J Pathol. 1994;145:1-6.
11. Jass JR, Cuzick J, Bussey HJR, Morson BC,
Northover JMA, Todd IP. The grading of rectal cancer: historical perspectives
and a multivariate analysis of 447 cases. Histopathology.
1986;10:437-439.
12. Hermanek P, Sobin LH. Colorectal
Carcinoma. In: Hermanek P, Gospodarowicz MK, Henson DE, Hutter RVP, Sobin LH,
eds. Prognostic Factors in Cancer.
New York, NY: Springer-Verlag NY Inc; 1995.
13. Hermanek P, Guggenmoos-Holzmann I, Gall
FP. Prognostic factors in rectal carcinoma. A contribution to the further
development of tumor classification. Dis
Colon Rectum. 1989;32:593-599.
14. Cooper HS. Surgical pathology of
endoscopically removed malignant polyps of the colon and rectum. Am J Surg Pathol. 1983;7:613-623.
15. Lipper S, Kahn LB, Ackerman LV. The
significance of microscopic invasive cancer in endoscopically removed polyps of
the large bowel. Cancer.
1983;52:1691-1699.
16. Morson BC,
Whiteway JE, Jones EA, Macrae FA, Williams CB. Histopathology and prognosis of
malignant colorectal polyps treated by endoscopic polypectomy. Gut. 1984;25:437-444.
17. Haggitt RC, Glotzbach RE, Soffer EE,
Wruble LD. Prognostic factors in colorectal carcinomas arising in adenomas:
implications for lesions removed by endoscopic polypectomy. Gastroenterology. 1985;89:328-336.
18. Cranley JP,
Petras RE, Carey WD, Paradis K, Sivak MV. When is endoscopic polypectomy
adequate therapy for colonic polyps containing invasive carcinoma? Gastroenterology. 1986:91:419-427.
19. Wilcox GM, Anderson PB, Colacchio TA. Early
invasive carcinoma in colonic polyps. A review of the literature with emphasis
on the assessment of the risk of metastasis. Cancer. 1986;57:160-171.
20. Richards WO, Webb WA, Morris SJ, et al.
Patient management after endoscopic removal of the cancerous colon adenoma. Ann Surg. 1987:205:665-672.
21. Wilcox GM, Beck JR. Early invasive cancer
in adenomatous colonic polyps (malignant polyps). Evaluation of the therapeutic
options by decision analysis. Gastroenterology.
1987;92:1159-1168.
22. Christie JP. Polypectomy or colectomy?
Management of 106 consecutively encountered colorectal polyps. Am Surg. 1988;54:93-99.
23. Cooper HS. The role of the pathologist in
the management of patients with endoscopically removed malignant colorectal
polyps. Pathol Annu, (Part 1).
1988;23:25-43.
24. Coverlizza S, Risio M, Ferrari, A,
Fenoglio-Preiser CM, Rossini FP. Colorectal adenomas containing invasive
carcinoma. Pathologic assessment of lymph node metastatic potential. Cancer. 1989;64:1937-1947.
25. Muller S, Chesner IM, Egan MJ, et al.
Significance of venous and lymphatic invasion in malignant polyps of the colon
and rectum. Gut. 1989;30:1385-1391.
26. Geraghty JM, Williams CB, Talbot IC.
Malignant colorectal polyps: venous invasion and successful treatment by
endoscopic polypectomy. Gut.
1991;32:774-778.
27. Nivatvongs S, Rojanasakul A, Reiman HM,
et al. The risk of lymph node metastasis in colorectal polyps with invasive
adenocarcinoma. Dis Colon Rectum.
1991;34:323-328.
28. Kyzer S, Bégin LR, Gordon PH, Mitmaker B.
The care of patients with colorectal polyps that contain invasive
adenocarcinoma. Cancer.
1992;70:2044-2050.
29. Cooper HS, Deppisch LM, Gourley WK, et
al. Endoscopically removed malignant colorectal polyps: clinicopathologic
correlations. Gastroenterology.
1995;108:1657-1665.
30. Volk EE,
Goldblum JR, Petras RE, Carey WD, Fazio VW. Management and outcome of patients
with invasive carcinoma arising in colorectal polyps. Gastroenterology. 1995;109:1801-1807.
31. Sobin LH, Wittekind C, eds. TNM
Classification of Malignant Tumours: International Union Against Cancer. 5th
ed., New York, NY: Wiley , 1997.
32. Chapuis PH, Dent OF, Fisher R, et al. A
multivariate analysis of clinical and pathological variables in prognosis after
resection of large bowel cancer. Br J
Surg. 1985;72:698-702.
33. Newland R, Dent O, Lyttle M, Chapuis PH,
Bokey EL. Pathologic determinants of survival associated with colorectal cancer
with lymph node metastases. A multivariate analysis of 579 patients. Cancer. 1994;73:2076-2082.
34. Shepherd N, Baxter K, Love S. The
prognostic importance of peritoneal involvement in colonic cancer: A
prospective evaluation. Gastroenterology.
1997;112:1096-1102.
35. Tominaga T, Sakabe T, Koyama Y, et al.
Prognostic factors for patients with colon or rectal carcinoma treated with
resection only. Five-year follow-up report. Cancer.
1996;78:403-408.
36. Zeng Z, Cohen AM, Hajdu S, Sternberg SS,
Sigurdson ER, Enker W. Serosal cytologic study to determine free mesothelial
penetration of intraperitoneal colon cancer. Cancer. 1992;70:737-740.
37. Knudsen JB, Nilsson T, Sprechler M,
Johansen A, Christensen N. Venous and nerve invasion as prognostic factors in
postoperative survival of patients with resectable cancer of the rectum. Dis Colon Rectum. 1983;26:613-617.
38. Michelassi F, Block GE, Vannucci L,
Montag A, Chappell R. A 5- to 21-year follow-up and analysis of 250 patients
with rectal adenocarcinoma. Ann Surg.
1988;208:379-387.
39. Minsky BD, Mies C, Rich TA, Recht A.
Lymphatic vessel invasion is an independent prognostic factor for survival in
colorectal cancer. Int J Radiat Oncol
Biol Phys. 1989;17:311-318.
40. Talbot IC, Ritchie S, Leighton MH, Hughes
AO, Bussey HJR, Morson BC. The clinical significance of invasion of veins in
rectal cancer. Br J Surg.
1980;67:439-442.
41. Talbot IC, Ritchie S, Leighton M, Hughes
AO, Bussey H, Morson BC. Invasion of veins by carcinoma of the rectum. Method
of detection, histologic features, and significance. Histopathology. 1981;5:141-163.
42. Blenkinsopp W, Stewart-Brown S, Blesovsky
L, Kearney G, Fielding LP. Histopathology reporting in large bowel cancer. J Clin Pathol. 1981;34:509-513.
43. Harrison JC, Dean PJ, El-Zekey F, Vander
Zwaag R. From Dukes through Jass:
Pathological prognostic indicators in rectal cancer. Hum Pathol. 1994;25:498-505.
44. Graham DM, Appelman HD. Crohn’s-like
lymphoid reaction and colorectal carcinoma: A potential histologic
prognosticator. Mod Pathol.
1990;3:332-335.
45. Harrison JC, Dean PJ, El-Zeky F, Vander
Zwaag R. Impact of Crohn’s-like lymphoid reaction on staging of right-sided
colon cancer: Results of multivariate analysis. Hum Pathol. 1995;26:31-38.
46. Carlon CA, Fabris G, Arslan-Pagnini C,
Pluchinotta AM, Chinelli E, Carniato S. Prognostic correlations of operable
carcinoma of the rectum. Dis Colon Rectum.
1985;28:47-50.
47. Jass JR, Atkin WS, Cuzick J, et al. The
grading of rectal cancer: historical perspectives and a multivariate analysis
of 447 cases. Histopathology.
1986;10:437-459.
48. Jass JR, Love SB, Northover JMA. A new
prognostic classification of rectal cancer. Lancet.
1987;1:1303-1306.
49. Shepherd NA, Saraga EP, Love SB, Jass JR.
Prognostic factors in colonic cancer. Histopathology.
1989;14:613-620.
50.