Diseases of the Colon & ReCtum Volume 57: 4 (2014)
BACKGROUND: the national Comprehensive Cancer
network recommends routine reevaluation of all stage ii
colon cancer specimens with fewer than 12 lymph nodes.
however, there are few data demonstrating the effect of
reevaluation on stage.
OBJECTIVE: the aim of this study was to demonstrate
the effect of pathologic reevaluation for colorectal cancers
with fewer than 12 lymph nodes on stage.
DESIGN: this study entailed a retrospective review of
SETTINGS: this study was conducted at 2 large
multispecialty referral centers.
INTERVENTIONS: Pathologic reevaluation was performed
to look for additional lymph nodes.
PATIENTS: all patients with stage i through iii colorectal
cancers with inadequate lymph node yields who
underwent reevaluation from January 1, 2007 through
march 31, 2011 were identified.
MAIN OUTCOME MEASURES: We recorded initial
pathologic stage and new stage following reevaluation.
the following variables before and after reevaluation
were also recorded: 1) total lymph node count, 2)
metastatic node count, 3) negative node count, and 4)
lymph node ratio.
RESULTS: eighty-three patients underwent pathologic
reevaluation from a total of 1682 cancer specimens. mean
nodal yields were 7.2 ± 2.6 on the first pathologic review.
on reevaluation, 80% of patients had one or more newly
identified nodes. on average, 6.9 ± 9.6 more lymph nodes
were identified with a metastatic node detected in 4
of 83 patients (4.8%). after pathologic reevaluation, 1
patient (1.2%) had a change in tnm stage from n1 to
n2 disease. the lymph node ratio changed in 13 of 15
patients (87% of stage iii cancers). only 4 of these had a
change in lymph node quartile.
LIMITATIONS: the study was limited by its retrospective
nature and small sample size.
CONCLUSION: few patients have a newly discovered
metastatic node or stage change following pathologic
reevaluation. the effect of pathologic reevaluation on
treatment and outcome should be further investigated.
KEY WORDS: lymph nodes; Colorectal cancer; Benchmark;
nodes examined, the presence of nodal metastasis, and the
number of negative lymph nodes, have all been correlated
with outcome.1–4 total lymph node harvest has become an
increasingly important predictor of outcome and quality
in colorectal cancer.2 the concept of a minimal threshold
of pathologically examined lymph nodes from colorec-
tal cancer resections was first introduced in 1990 by the
World Congress of Gastroenterology.5 however, since that
here is little controversy surrounding lymph node
status as an important prognostic factor for sur-
vival in colorectal cancer. the total number of
Does Reevaluation of Colorectal Cancers With
Inadequate Nodal Yield Lead to Stage Migration or
the Identification of Metastatic Lymph Nodes?
lilian Chen, m.D.1 • Matthew F. Kalady, M.D.2 • John Goldblum, M.D.2
Dilara Seyidova-Khoshknabi, M.D.2 • Eric J. Burks, M.D.1 • Patricia L. Roberts, M.D.1
Rocco Ricciardi, m.D., m.P.h.1
1 Department of Colon and Rectal surgery, lahey Clinic, Burlington, massachusetts
2 Department of Colorectal surgery, Digestive Disease institute, Cleveland Clinic, Cleveland, ohio
Dis Colon Rectum 2014; 57: 432–437
© the asCRs 2014
Financial Disclosures: none reported.
Presented at the meeting of the american College of surgeons, Chicago,
il, september 30 to october 4, 2012.
Correspondence: Rocco Ricciardi, m.D., mPh, Department of Colon
and Rectal surgery, lahey Clinic, assistant Professor of surgery, tufts
university, 41 mall Rd, Burlington, ma 01805. e-mail: rocco.ricciardi@
Diseases of the Colon & ReCtum Volume 57: 4 (2014)
time, the minimal number of examined nodes for accurate
staging has been debated throughout the literature with
recommendations ranging from 6 to more than 40 lymph
in 2007, the american College of surgeons Commis-
sion on Cancer, the american society of Clinical oncol-
ogy, and the national Comprehensive Cancer network
recommended that at least 12 regional lymph nodes
should be removed and pathologically examined for re-
sected colorectal cancers.17 this quality threshold was then
endorsed by the national Quality forum in april 2007, the
nation's clearinghouse for quality measures.18 since then,
insurers as well as others have applied this standard as a
quality benchmark, directing referrals to centers that meet
efforts to increase lymph node yields are now wide-
spread. no standard pathologic reevaluation method
exists, although a variety of fat-clearing and fixation tech-
niques have been described.20 at this time, for those in-
stances in which a stage ii colon cancer has fewer than12
lymph nodes identified, the national Comprehensive
Cancer network guidelines recommend routine patho-
logic reevaluation with the submission of more tissue for
potential lymph node identification.21 Despite these rec-
ommendations, there are few data that pathologic restag-
ing has any affect on final pathologic stage or oncologic
outcomes. the aim of our study was thus to demonstrate
the effect of pathologic reevaluation for colorectal cancers
with inadequate lymph node yields on stage.
We conducted a retrospective review of all pathology re-
ports of patients with american Joint Committee on Can-
cer (7th edition) stage i through iii colorectal cancers
from the lahey Clinic and Cleveland Clinic. We included
patients who underwent neoadjuvant chemoradiation for
rectal cancers and those with complete pathologic response
(ypt0n0) after neoadjuvant therapy. all patients who un-
derwent colorectal procedures between January 1, 2007
and march 31, 2011 were evaluated. Patients with fewer
than 12 lymph nodes who did not have pathology records
stating reevaluation were excluded from our study. in ad-
dition, patients with carcinoma in situ, stage iV colorectal
cancers, or colorectal cancers other than adenocarcinoma
were excluded. Cancers of the appendix, anus, anal canal,
and anorectum were not evaluated.
Standard Pathologic Review Protocol
lymph nodes for colorectal specimens were harvested in a
standard fashion. Pericolonic adipose tissue was removed
from the bowel wall after formalin fixation. the adipose
tissue was thinly sectioned, and each slice was palpated for
areas of induration that were then evaluated histologically
by routine hematoxylin and eosin staining after process-
ing and paraffin embedding. in cases where fewer than
12 lymph nodes were observed, additional sampling of
the previous slices of adipose tissue was performed after
prolonged formalin fixation. in cases where induration
was not observed, fibrovascular structures were submit-
ted in several blocks with the hope of finding microscopic
lymph nodes on histologic review. fat-clearing solutions
were used when appropriate. the number of sections per
pathologic specimen varied by institution.
the surgical procedure was performed either laparoscopi-
cally or with open traditional techniques. Both institu-
tions stressed the value of en bloc high ligation of the
named feeding vessel to the tumor. During the time frame
of this study, all rectal cancer procedures were conducted
with attention to autonomic nerve preservation and to-
tal mesorectal excision for distal rectal cancers or partial
mesorectal excision for mid to upper cancers. Procedures
were performed to at least meet the 12-lymph-node mini-
mum harvest recommended by the national Comprehen-
sive Cancer network.21
Review of Specimens With Fewer Than 12 Lymph Nodes
all pathology reports with inadequate lymph node yield
(fewer than 12 nodes) that underwent reevaluation at the
request of the pathologist, surgeon, or oncologist were
identified. no formal guidelines as to when reevaluation
should be performed were used by either institution. how-
ever, the reevaluation was encouraged when fewer than 12
lymph nodes were identified. an annotation that further
review was performed because of inadequate initial assess-
ment or an addendum to the original pathology note was
used as indication of “reevaluation.”
the patient’s staging was standardized to the american
Joint Committee on Cancer (7th edition) tnm colon
and rectum cancer staging system. We recorded the initial
pathologic stage and the new stage following reevaluation.
We also recorded the following variables before and after
reevaluation: 1) total lymph node count, 2) metastatic
node count, 3) negative node count, and 4) lymph node
ratio for stage iii cancers. the lymph node ratio was cal-
culated by dividing positive lymph nodes by total lymph
node counts. We then identified quartiles of lymph node
ratios as defined by Wang et al22 where lymph node ratio
groups lnR1 through lnR4 were defined as <0.07, 0.07
to 0.25, 0.25 to 0.50, and 0.50 to 1.0.
Chen et al: lYmPh noDe thResholDs
a total of 1682 patients underwent colorectal cancer resec-
tions during the 39-month study period at the 2 institutions.
eighty-three patients underwent pathologic reevaluation
after initial inadequate lymph node harvest. the study
group age ranged from 34 to 97 years with a mean age of
68 ± 14 years. there were 55 male and 28 female patients.
tumor location was identified as colonic in 48%, whereas
52% of tumors were rectal cancers. approximately 88% of
all patients with rectal cancer had some element of neoad-
juvant therapy (short or long course). a subset of 20 pa-
tients did not have pathologic reevaluation despite having
inadequate lymph node yields. these patients were similar
to the group that had pathologic reevaluation with respect
to demographics, tumor location, and stage.
on initial pathologic review, mean nodal yields were
7.2 ± 2.6 (0.3 ± 0.8 metastatic nodes and 6.9 ± 2.8 negative
nodes). the initial pathologic review revealed 39 (47%)
stage i cancers, 28 (34%) stage ii cancers, and 15 (18%)
stage iii cancers. one patient (1%) had complete patho-
logic response after neoadjuvant chemoradiation for rec-
of the total group of 83 patients, 80% of patients
had 1 or more newly identified nodes on reevaluation.
on average, 6.9 ± 9.6 more lymph nodes were identified
on reevaluation (0.1 ± 0.4 metastatic nodes and 6.8 ± 9.6
negative nodes) (fig. 1). a metastatic node was identi-
fied in 4 of 83 patients (4.8%). Despite the large number
of nodes identified, 37 (45%) patients remained below
the 12-lymph-node benchmark. from the subset of only
stage ii patients, 14 (50%) patients remained below the
after pathologic reevaluation, 1 patient (1.2%) had a
change in tnm stage from n1 disease to n2 disease. this
stage, however, remained a clinical stage iiib cancer. af-
ter pathologic reevaluation, staging remained 47% stage
i cancers, 34% stage ii cancers, and 18% stage iii cancers.
no pathologic upstaging resulted from our reevaluation.
of the 28 patients with stage ii cancers (34% of our study
population), no metastatic lymph node was found on
lymph node ratios were calculated for patients with
stage iii cancer before and after reevaluation. the lymph
node ratio changed in 13 of 15 patients (87% of stage iii can-
cers). of these, 4 (31%) had a change in quartile (table 1).
in this study of 1682 patients at 2 large specialty centers, we
evaluated the effect of pathologic reevaluation of colorec-
tal cancers with fewer than 12 lymph nodes on stage. our
study revealed that pathologic reevaluation after inad-
equate nodal harvest as recommended by the national
Comprehensive Cancer network yielded a large number
of negative lymph nodes and very rarely a metastatic node.
ultimately, pathologic reevaluation led to no upstaging of
colorectal cancer stage at final reporting.
in colorectal cancer, the number of lymph nodes ex-
amined is associated with survival and is independent of
other known prognostic factors. it is for this reason that
a lymph node count of 12 has been proposed as a marker
of quality care in colorectal cancer.1,17 however, there are
a substantial number of patients who do not have lymph
node yields that meet these criteria.23–25 there are proba-
bly a number of reasons for inadequate lymph node yields,
Number of lymph nodes before and after reevaluation
Number of lymph nodes
FIGURE 1. Graph of lymph node yield before and after reevaluation. Results are mean total yields, negative nodal yields, and metastatic nodal
yields before and after pathology reevaluation.
Diseases of the Colon & ReCtum Volume 57: 4 (2014)
including tumor characteristics, tumor biology, surgeon,
and patient factors, as well as the pathologic evaluation of
the surgical specimen. a number of studies have sought to
identify factors, including one by Jakub et al26 that revealed
that age, primary tumor site, cancer stage, and year of sur-
gery were all significantly associated with the number of
lymph nodes retrieved.
in 2007, the national Cancer Care network recom-
mended routine reevaluation of all stage ii colon cancer
specimens with fewer than 12 lymph nodes.21 the evi-
dence basis for this recommendation was unclear, with the
exception of the understanding of the robust relationship
between lymph node yield and outcome. Given the lack of
clear evidence for reevaluation, we conducted this study
to identify the value of pathologic reevaluation. We found
that despite careful and thorough pathologic reevaluation,
few patients have a newly identified metastatic node on
review. additionally, reevaluation did not have any effect
on cancer stage as one might expect. however, reevalua-
tion did yield almost double the initial lymph node count,
increasing the total lymph node count on final reporting.
in this study, we included patients with tumors ranging
from complete response to stage iii and a location of colon
or rectum. however, it should be clear that the national
Comprehensive Cancer network recommends pathologic
reevaluation for stage ii colon cancers with fewer than 12
lymph nodes.21 our inclusion of all nonmetastatic adeno-
carcinomas and those tumors of the rectum (52%) was to
evaluate the role of reevaluation on all colorectal tumors
and to increase the size of our sample. Yet, the only patient
with a shift in n1 to n2 disease had rectal cancer and un-
derwent neoadjuvant therapy. the consistency of the find-
ing of no tumor upstaging despite variable tumor location
and stage might help us to better understand the mecha-
nism behind the association between lymph node harvest
and survival. thus, it appears from our data, that increas-
ing lymph node yield beyond what is initially identified on
pathology is unlikely to improve survival. the theory that
increased survival with high lymph node yields is due to
upstaging (and the benefits of adjuvant therapy) is likely
without merit. the improved survival is more likely to be
associated with the extent of curative surgery or, poten-
tially, an immunological mechanism.
in our study, we did found that pathologic reevaluation
yielded additional lymph nodes and hence a change in the
lymph node ratio of our stage iii colorectal cancers. Wang
et al found that lymph node ratio was an independent pre-
dictor of survival after adjusting for patient’s age, tumor
size, tumor grade, race, number of positive lymph nodes,
and total lymph nodes harvested. in his study, he found
that lymph node ratio was a more accurate prognostic
indicator for patients who had stage iii colon cancer and
proposed a new classification algorithm for stage iii co-
lon cancers.22 the observed 5-year survival for increasing
quartiles of lymph node ratios was 64.8%, 56.2%, 45.1%,
and 29.6%.22 our analysis of lymph node ratios demon-
strated that 13 of 15 (87%) stage iii patients had a change
in their lymph node ratio. of those with a change in ratio,
only 4 patients had a decline in their lymph node quartile,
representing an improvement in reported outcome ac-
cording to Wang’s classification. thus, reevaluation may
have some prognostic value in identifying patients who
might have a better prognosis and might serve as an im-
portant educational point in patient discussions.
our data do not indicate that we should abandon
pathologic reevaluation. as previously stated, there may be
value in identifying negative lymph nodes for prognostic
purposes.2 however, following pathologic reevaluation, no
patient had a change in stage or change in management. ev-
idence basis should be used when possible in directing pa-
TABLE 1. Lymph node ratio and migration in quartiles
PatientsInitial ratio (%)Final ratio (%)Change in ratioChange in quartileQuartile change
LNR2 to LNR1
LNR3 to LNR2
LNR2 to LNR1
LNR4 to LNR2
Quartiles as defined by Wang et al.22 Observed 5-year survival for increasing quartiles of lymph node ratios was 64.8%, 56.2%, 45.1%, and 29.6%. LNR quartiles: LNR1, <7%;
LNR2, 7%–25%; LNR3, 25%–50%; LNR4, 50%–100%.
LNR = lymph node ratio; Y, yes; N, no.
Chen et al: lYmPh noDe thResholDs
tient care as well as when considering quality benchmarks
or guidelines. our data indicate that there is little evidence
to mandate pathologic reevaluation in patients with inad-
equate lymph node yields. a goal of obtaining an adequate
lymph node count is important and certainly based on evi-
dence. But, the total lymph node yield should be the total
lymph nodes present in the specimen, which will likely vary
based on a number of the factors described above.
our study has limitations based on the nature of the
study design. the pathology specimen processing was not
standardized across our 2 institutions and a list of 20 pa-
tients were never reevaluated despite having less than the
benchmark of 12 lymph nodes. it is unclear why those pa-
tients were not reevaluated, but the data do indicate that
they had similar tumor and patient characteristics as the
patients that did meet study inclusion criteria. our pa-
tient population was derived from 2 large multispecialty
clinics with substantial knowledge and expertise in the
management of colorectal cancer. the group of surgeons,
pathologists, oncologists, and pathology technicians in-
volved in this patient population was well versed in the
understanding of the 12-lymph-node quality metric and
associated outcome. although our initial study population
was large, the total number of patients who met study en-
try criteria was quite small. therefore, a larger sample size
may uncover more patients with metastatic lymph nodes
on pathologic reevaluation. in addition, given the subspe-
cialty practice of the group involved, generalizability may
also be a concern. Bilimoria et al,19 in 2008, examined the
use of a 12-node minimum as a national hospital report
card. they found that, according to the national Cancer
Database, the majority of colorectal cancers (about 75%)
were treated in community hospitals. thus, repeating our
study with multiple centers may render the study findings
more applicable to the us population.
We found little value in pathologic reevaluation for patients
with colorectal cancer who have inadequate lymph node
counts. our study did not aim to address the validity of the
12-lymph-node minimum. instead, our aim was to deter-
mine the value and effect of routine reevaluation of speci-
mens with fewer than 12 lymph nodes as recommended
by the national Comprehensive Cancer network. thus, al-
though we can demonstrate that reevaluation increases to-
tal lymph node harvests, this practice is not associated with
a meaningful change in patient cancer stage. ultimately, the
effect of pathologic reevaluation on patient cancer treat-
ment and outcome should be further investigated.
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