Colon cancer staging

Ricard Masia, M.D. Ph.D.

Gastrointestinal Pathology Unit
Massachusetts General Hospital

Wednesday, May 8th 2018

 AJCC 8 th edition
• The new edition of the AJCC
Cancer Staging Manual (8th
edition) was released in October
2016
• Initially scheduled to go into effect
in March 2017 but delayed until
January 1st, 2018
• Allowed CAP to release updated
colon cancer protocol incorporating
changes
 Changes affecting reporting
of colorectal cancer
• Adoption of a 4-tier grading system
• Two new histologic variants
• Reporting of tumor budding
• M1c stage for peritoneal metastases

Plus some new language to clarify existing concepts

 Colorectal Cancer (CRC)
• CRC is one of the most common cancers worldwide and a leading
cause of mortality
• 3rd in incidence, 4th in deaths in 2013 worldwide
• Risk factors include age, genetic predisposition, and environmental factors
(nutrition, smoking)
• Treatment approach: surgery +/- postoperative chemotherapy
depending on pathologic stage and other features
• Rectal cancers generally treated with preoperative chemotherapy +
radiation, then surgery
 Role of the pathologist in CRC
• Endoscopic biopsy:
• Is there submucosal invasive carcinoma?  diagnosis of CRC
 Invasive CRC on biopsy
• Submucosal invasive carcinoma (pT1) carries risk of nodal and/or
distant metastasis
• If mass lesion is present endoscopically: surgery
• If found within a polyp, it is adequately treated by polypectomy unless:
• Invasive CRC is high-grade
• There is lymphatic or vascular invasion
• Invasive CRC is close to margin (<0.1-0.2 cm)

• Diagnostically, most helpful feature is stromal desmoplasia

• Presence of muscularis mucosae or submucosal vessels may also help
 Morphology of CRC
• ~90% of CRC is a conventional gland-forming adenocarcinoma
• Tall/columnar cells forming medium-sized to large glands, often with
intraluminal “dirty” necrosis

• The remainder consists of histological variants; several of these

are recognized by the WHO
 Grading of conventional CRC

• Grade is based on the percentage of tumor that forms glands

• Histologic grade is an important prognostic factor in many studies,
with strong correlation between poor differentiation and adverse
outcome
• AJCC 7th ed. used a 2-tier system:
• Low-Grade: >50% of the tumor forms glands
• High-Grade: <50% of the tumor forms glands
• The AJCC has decided to use a 4-tier grading system in the 8th
ed.
• Most studies have stratified CRC grade into a 2-tier (low-
grade/high-grade) system, and argued that subdividing low-grade
further (into well and moderately differentiated) does not provide
additional prognostic information
• However, a 3- or 4-tier system is generally used for GI tract
carcinomas, and thus using a 4-tier grading system for CRC
brings it into alignment with the rest of the GI tract
 4-tier grading system
• Well differentiated (>95% gland formation)
• Moderately differentiated (50-95% gland formation)
• Poorly differentiated (<50% gland formation)
• Undifferentiated – no gland formation

Grade
GX Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
G4 Undifferentiated
 Histologic variants
• Adenocarcinoma
• Mucinous (colloid) adenocarcinoma (>50% mucin)
• Signet ring cell carcinoma (>50% signet ring cells)
• Medullary carcinoma
• Micropapillary carcinoma (new)
• Serrated adenocarcinoma (new)
• Squamous cell carcinoma
• Adenosquamous carcinoma
• High-grade neuroendocrine carcinoma (small cell carcinoma or large
cell neuroendocrine carcinoma)
• Mixed adenoneuroendocrine carcinoma
• Undifferentiated carcinoma
 Micropapillary carcinoma
• Small tight clusters of tumor cells in cleft-like spaces
• Often present in association with conventional adenocarcinoma
• Strongly associated with lymphovascular invasion and lymph
node metastasis
 Serrated adenocarcinoma
• Neoplastic glands showing prominent serrations, tumor cells with
basal nuclei and eosinophilic cytoplasm, and no or minimal
luminal necrosis
• Thought to be related to traditional serrated adenomas and may
have a more aggressive course than conventional
adenocarcinoma
Garcia-Solano J et al.
Hum Pathol 41(10):
1359-68, 2010
 Histologic variants
• Associated with worse prognosis: undifferentiated carcinoma,
signet ring cell carcinoma

• Associated with Microsatellite Instability (MSI): medullary

carcinoma, mucinous carcinoma
• When stage-matched to MSS tumors, MSI tumors have better prognosis
but worse response to 5-FU-based chemotherapy
• This is true for sporadic MSI tumors (~85%) as well as HNPCC-associated
MSI tumors (~15%)
 Role of the pathologist in CRC
• Endoscopic biopsy:
• Is there submucosal invasive carcinoma?  diagnosis of CRC

• Resection specimen:
• 1) Assessment of margins
Provides prognosis
• 2) pTNM staging
Guides postoperative treatment
• 3) Other pathologic data: grade, LVI

The pathologic stage of disease as described by pTNM system

is the most important prognostic factor in CRC
 Surgical margins

• Proximal and distal are unlikely

to be involved
• Radial is the most important for
prognosis
• Aka lateral, circumferential
• Present in all specimens! Nature of
radial margin will depend on
segment of colon resected
 Identifying the radial margin
Colon Segment Serosa Mesentery Omentum Radial
Margin
(Ileum and appendix) + + - M
Cecum + - - -
Ascending colon + -/+ - R
Transverse colon + + + M/O
Descending colon + -/+ - R
Sigmoid colon + + - M
Rectum +/- - - R

M: mesentery, R: retroperitoneal soft tissue, O: omentum

 Examples of radial margins
Radial margin
(mesenteric)
Radial margin
(retroperitoneal soft
tissues); no serosa

Serosa

Sigmoid colon Distal rectum

• Radial margin should not be confused with serosa, which is a peritonealized

surface (anatomic structure)

Adapted from CAP protocol

 T stage: primary tumor
Primary tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor
Carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no
Tis
extension through muscularis mucosae)
Tumor invades the submucosa (through the muscularis mucosa but not into the
T1
muscularis propria)
T2 Tumor invades the muscularis propria
T3 Tumor invades through the muscularis propria into pericolorectal tissues
Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or
T4
structure
Tumor invades through the visceral peritoneum (including gross perforation of the bowel
T4a through tumor and continuous invasion of tumor through areas of inflammation to the
surface of the visceral peritoneum)
T4b Tumor directly invades or adheres to adjacent organs or structures
 pT4a stage

• Serosal involvement (pT4a) can be difficult to assess, and is likely

under-diagnosed

• In general, either of the following is considered definite evidence

of pT4a:
• Infiltrating tumor present at serosal surface with inflammatory reaction,
mesothelial hyperplasia, and/or erosion/ulceration
• Free tumor cells on serosal surface with underlying ulceration of the
visceral peritoneum
 pT4a stage
• Some also consider tumor close to, but not at, the serosal surface
enough for pT4a if there is associated inflammatory reaction or
mesothelial hyperplasia
• In this setting, have a high suspicion for pT4a!
• Get deeper levels, consider an elastic stain, re-examine gross specimen
and consider taking additional sections of tumor to serosa

• In equivocal cases, it is probably best to err on the side of pT4a

so that additional therapy remains an option for the patient
Deeper level
Elastic tissue stain may help identify serosal penetration (breaching
of peritoneal elastic lamina) – but not widely adopted

Liang WY et al. Am J Surg Pathol 37(1):1565-70, 2013

 pT4a vs. positive radial margin
• Tumor penetration of serosa (pT4a) is different from pT3 tumor
with a positive radial margin
• Serosa is an anatomic structure. Tumor penetration of it reflects
biological behavior of the tumor, but not the adequacy of surgery
(you can have a pT4a tumor with negative margins)
• A positive radial margin reflects adequacy of surgery (surgeon
was unable to clear all tumor from the patient) but does not
constitute pT4a
 pT4a vs. positive radial margin

Serosa-covered
(peritonealized) segment
pT4a
Negative radial margin

Non serosa-covered
(nonperitonealized) segment
pT3
Positive radial margin

CAP protocol
 N stage: regional lymph nodes
Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis

One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm),
N1
or any number of tumor deposits are present and all identifiable lymph nodes are negative

N1a One regional lymph node is positive

N1b Two or three regional lymph nodes are positive

No regional lymph nodes are positive, but there are tumor deposits in the
 subserosa
N1c
 mesentery
 or nonperitonealized pericolic, or perirectal/mesorectal tissues.

N2 Four or more regional nodes are positive

N2a Four to six regional lymph nodes are positive
N2b Seven or more regional lymph nodes are positive
 Importance of the nodal stage
AJCC Stage Groupings
Stage 0 Tis N0 M0
Stage I T1 N0 M0 • In general: stage I-II patients are not
T2 N0 M0 offered postop chemo, while stage
Stage IIA T3 N0 M0
Stage IIB T4a N0 M0
III-IV patients are
Stage IIC T4b N0 M0 • Stage III is defined as having
Stage IIIA T1-T2 N1/N1c M0
T1 N2a M0
positive nodes – independently of T
Stage IIIB T3-T4a N1/N1c M0 stage
T2-T3 N2a M0
T1-T2 N2b M0
• The nodal stage is a major
Stage IIIC T4a N2a M0 determinant of whether the patient
T3-T4a N2b M0 receives postoperative treatment
T4b N1-N2 M0
Stage IVA Any T Any N M1a
Stage IVB Any T Any N M1b
Stage IVC Any T Any N M1c
• Some stage II patients will also be offered chemo – referred to as
“stage II with high-risk”:
• High-grade, pT4, lymphovascular invasion, PNI, or close/positive margins
• Fewer than 12 nodes examined – this means the oncologist does not
“trust” the nodal stage and is treating the patient as though they had nodal
mets that were missed by the pathologist!

• A reliable node stage is very important in tumors with low-T stage

and no high-risk features
 How many lymph nodes are needed?

• The probability of finding nodal metastases increases with the

number of nodes examined
• Many studies have shown that examining too few lymph nodes leads to
understaging
• The nodal stage starts becoming reliable when 12-15 nodes are examined

• As a general rule, 15 nodes is a reasonable target number

(although there is no minimum; always sample as many nodes as
possible)
 Getting to 15 nodes
• It is not always possible to get to 15 nodes; however, at the very
least you should try to get to 15 before signing out the case
• Several options: do a repeat node dissection, submit pericolonic fat, use
dissect-aid solution…
• Shows surgeon and oncologist that you understand the importance of
proper nodal staging in CRC
Node jar
 Tumor deposits
• A tumor deposit (aka peritumoral deposit or satellite nodule) is a
discrete deposit of tumor within the pericolonic or perirectal fat,
away from the leading edge of the tumor, without histologic
evidence of residual lymph node
• May represent discontinuous spread of tumor, lymphovascular
spread with extravascular extension, or completely replaced
lymph nodes
• The way tumor deposits are classified in the TNM system has
changed over time
 Staging tumor deposits
• N1c category can only be used when there are no lymph node
metastases
• If both positive nodes and tumor deposits are present, use N
stage corresponding only to the number of positive nodes present
– do not add tumor deposits to number of positive nodes
• Also specify number of tumor deposits in the report
• At our institution, pN1c patients tend to be treated similarly to patients
with nodal metastases
 Isolated Tumor Cells (ITCs)

• Defined as single tumor cells or small clusters of tumor cells

measuring <0.2 mm, often but not always detected by IHC
• Exact significance of ITCs is unclear, but by themselves they do
not affect prognosis, so do not count towards the N stage
• If only ITCs present within lymph nodes: stage as N0
• Should mention presence of ITCs in report
 Peritumoral tumor budding
• Tumor budding: presence of single cells or small clusters of up to
5 cells at the advancing front of the tumor
• In carcinoma arising in a polyp: high tumor budding is a significant
risk factor for nodal metastases
• High tumor budding is also associated with worse prognosis in
stage II patients; some advocate it as a high risk factor (justifying
postoperative chemotherapy)
• Not a required element, but recommended for cancers arising in
polyps and for stage I-II cases
 Assessing tumor budding
• Do counts on H&E sections, not IHC
• You can use IHC to select the area to count – but count on H&E only

• Choose one ‘hotspot’ after reviewing all available slides with

invasive tumor
• Report total number of buds in an area measuring 0.785 mm2
• One 20x field area is 0.785 mm2 in some scopes, but not all
• In others, it is 0.95 mm2, so need to multiply by 0.8 and round to nearest
whole number

• Report total number of buds as well as a 3-tier score: low (1-5

buds), intermediate (6-9 buds), and high (10 or more buds)
 Reporting tumor budding
Peritumoral tumor budding:
• Absent
• Present

If present, number of tumor buds in one ‘hotspot’ field (absolute

number in area=0.785 mm2): ____
• Low score (1-5)
• Intermediate score (6-9)
• High score (10 or more)
 M stage
• Added separate pM1c stage to highlight poor prognosis of
peritoneal carcinomatosis
• Clarified that M0 is not assigned by pathologists – do not use it!

Distant metastases

No distant metastasis by imaging, etc.; no evidence of tumor in distant sites or organs (This
M0
category is not assigned by pathologists.)

M1 Metastasis to one or more distant sites or organs or peritoneal metastasis is identified

M1a Metastasis to one site or organ is identified without peritoneal metastasis
M1b Metastasis to two or more sites or organs is identified without peritoneal metastasis

M1c Metastasis to the peritoneal surface is identified alone or with other site or organ metastases
Additional pathologic features that
have prognostic value
These are associated with worse prognosis:
• Lymphatic/small vessel invasion (LVI)
• Perineural invasion (PNI)
• Large vessel (venous) invasion
 Large vessel invasion
• Large vessel (venous) invasion is associated with worse
prognosis
• Invasion of extramural veins, in particular, is an independent
indicator of unfavorable outcome and increased risk of hepatic
metastasis; thus, you should specify whether venous invasion is
submucosal/intramural or extramural
• Foci of venous invasion may appear as rounded tumor nodules
adjacent to “orphan arteries”
• Elastic tissue stain may help highlight venous invasion
 Rectal tumors
• Rectal tumors are managed differently:
• Usually treated with preoperative chemoradiation
• Surgically removed as Total Mesorectal Excision (TME) specimens
• In TME, surgeon carries out sharp dissection along the plane of
the visceral mesorectal fascia (mesorectal plane) to remove
mesorectum
• This is technically challenging due to the narrow working space in the
pelvis, which makes it hard for the surgeon to stay “out” in the mesorectal
plane as dissection proceeds distally
 The TME specimen
• The 2 most important factors in predicting local recurrence and
overall survival in rectal cancer:
• Quality of mesorectal excision
• Status of radial margin
• The way TME specimens are handled reflects the importance of
these two parameters
 Assessing quality of mesorectal
excision by gross examination
Mesorectal Surface
Grade Defects in Mesorectum Coning Radial Margin
and Bulk
Good bulk, smooth
Complete No deeper than 5 mm None Smooth
surface
Deeper than 5 mm but no
Nearly Moderate bulk, visible muscularis propria Moderately
Moderate
complete irregular surface (except where levator irregular
muscles insert)

Little bulk, irregular Moderate to

Incomplete Down to muscularis propria Irregular
surface marked
 Quality of mesorectal excision is assessed by gross examination

Complete

Sectioned
perpendicular
Incomplete to long axis

Campa-Thompson M et al. Clin Colon Rectal Surg 2015

Survival in patients with rectal adenocarcinoma
with negative margins

Nagtegaal ID et al. J Clin Oncol 20(7):1729-34, 2002