Tumor deposits in colorectal cancer: Refining their definition in the TNM system

Abstract

Tumor deposits (TDs) are discontinuous tumor spread in the mesocolon/mesorectum which is found in approximately 20% of colorectal cancer (CRC) and negatively affects survival. We have a history of repeated revisions on TD definition and categorization in the tumor-node-metastasis (TNM) system leading to stage migration. Since 1997, TDs have been categorized as T or N factors depending on their size (TNM5) or contour (TNM6). In 2009, TNM7 provided the category of N1c for TDs in a case without positive lymph nodes (LNs), which is also used in TNM8. However, increasing evidence suggests that these revisions are suboptimal and only “partially” successful. Specifically, the N1c rule is certainly useful for oncologists who are having difficulty with TDs in a case with no positive LNs. However, it has failed to maximize the value of the TNM system because of the underused prognostic information of individual TDs. Recently, the potential value of an alternative staging method has been highlighted in several studies using the “counting method.” For this method, all nodular type TDs are individually counted together with positive LNs to derive the final pN, yielding a prognostic and diagnostic value that is superior to existing TNM systems. The TNM system has long stuck to the origin of TDs in providing its categorization, but it is time to make way for alternative options and initiate an international discussion on optimal treatment of TDs in tumor staging; otherwise, a proportion of patients end up missing an opportunity to receive the optimal adjuvant treatment.

Full text

Ann Gastroenterol Surg. 2023;7:225–235.
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225www.AGSjournal.com
1 | INTRODUCTION
Tumor staging in conventional pathological investigation is still at
the center of clinical reporting on colorectal cancer (CRC) even in the
precision medicine era . A recent milestone s tudy by the International
Duration of Adjuvant Chemotherapy (IDEA) collaboration high-
lighted the importance of the sub- staging of stages II and stage III
in determining an adjuvant chemotherapy regimen for individual pa-
tients.1,2 Currently, T and N stages are unprecedentedly important
as they determine the selection of patients for the chemotherapy
regimen, thereby determining patient clinical outcomes.3
Tumor deposits (TDs) were isolated tumor lesions in the regional
lymphatic area other than those in the lymph nodes, which were first
noticed in the 1980s by some pathologists, such as Jass and Morson.
Received: 30 Octobe r 2022
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Revised: 23 Nove mber 2022
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Accepted: 22 December 202 2
DOI: 10.1002/ags3 .12652
REVIEW ARTICLE
Tumor deposits in colorectal cancer: Refining their definition in
the TNM system
Hideki Ueno1 | Iris D. Nagtegaal2 | Philip Quirke3 | Kenichi Sugihara4 | Yoichi Ajioka5
This is an op en access ar ticle under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provide d the original work is properly cited.
© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & S ons Australia, Ltd on behalf of The Japa nese Society of
Gastroenterological Surgery.
1Department of Surgery, National Defense
Medical College, Saitama, Japan
2Depar tment of Pathology, Radb oud
University Medical Centre, Nijmegen, The
Netherlands
3Divisio n of Patholog y and Data Analytic s,
University of Leeds, St James's Uni versity
Hospit al, Leeds, UK
4Depar tment of Surgical Oncology, Tokyo
Medical and Dental Universit y, Graduate
School of Medical and Dental Sci ences,
Tokyo, Japan
5Divisio n of Molecular and Diagnos tic
Pathology, Niigata University Graduate
School of Medical and Dental Sci ences,
Niigata, Japan
Correspondence
Hideki Ueno, Department of Surgery,
National Defense Medical College, 3- 2
Namiki, Tokorozawa, Saitama 359- 8513,
Japan.
Email: ueno_surg1@ndmc.ac.jp
Abstract
Tumor deposits (TDs) are discontinuous tumor spread in the mesocolon/mesorectum
which is found in approximately 20% of colorectal cancer (CRC) and negatively affects
survival. We have a history of repeated revisions on TD definition and categoriza-
tion in the tumor- node- metastasis (TNM) system leading to stage migration. Since
1997, TDs have been categorized as T or N factors depending on their size (TNM5)
or contour (TNM6). In 2009, TNM7 provided the category of N1c for TDs in a case
without positive lymph nodes (LNs), which is also used in TNM8. However, increasing
evidence suggests that these revisions are suboptimal and only “partially” successful.
Specifically, the N1c rule is certainly useful for oncologists who are having difficulty
with TDs in a case with no positive LNs. However, it has failed to maximize the value
of the TNM system because of the underused prognostic information of individual
TDs. Recently, the potential value of an alternative staging method has been high-
lighted in several studies using the “counting method.” For this method, all nodular
type TDs are individually counted together with positive LNs to derive the final pN,
yielding a prognostic and diagnostic value that is superior to existing TNM systems.
The TNM system has long stuck to the origin of TDs in providing its categorization,
but it is time to make way for alternative options and initiate an international discus-
sion on optimal treatment of TDs in tumor staging; otherwise, a proportion of patients
end up missing an opportunity to receive the optimal adjuvant treatment.
KEYWORDS
Extramural cancer deposits without lymph node structure (EX ), Lymph node metastasis, Tumor
deposits (TDs), tumor stage, Tumor- node- metastasis (TNM) system

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They described that “the clinical importance of this observation is
unknown at present.”4 The TDs were first adopted in the Union for
International Cancer Control (UICC)'s TNM classification 5th edition
in 1997 as a staging factor (Table 1).5 Since then, pathological prac-
tice for TDs has been revised in every revision of the TNM staging
system until its 8th edition (2017). However, uncer tainty remained in
TD definition and categorization in the tumor staging system. Over
time, considerable new data around TDs has accumulated, which
should now guide us in the optimization of the TNM staging system.
2 | PROGNOSTIC IMPACT OF TDS
Early studies of the prognostic impact of TDs date back to the 1990s.
Harrison et al. investigated metastatic tumor nodules in perirectal or
pericolic fat with the definition of “discrete aggregates of carcinoma
within fibroadipose tissue unassociated with recognizable lymph
node (LN) structure and not contiguous with the mural component
of invasive carcinoma” and showed that such lesions adversely af-
fected the prognosis in rectal cancer (1994)6 and right- sided colon
cancer (1995).7 In 1997, Ueno and Mochizuki first r eported the ac tual
status of discontinuous cancer- spread lesions based on the system-
atic investigation of the lymph drainage area of a primar y carcinoma,
i.e., not only extramural adipose tissue attached to the bowel but
also adipose tissue of the regional lymphatic area that was postop-
eratively harvested for pathologic examination of LNs (Figure 1).8
Their study reported a 26% incidence rate of such lesions in patients
with curative resection and 66% in those with non- curative resec-
tion. They categorized the discontinuous lesions into four patterns:
scattering, vessel invasion, neural invasion, and nodular type, and all
types notably exer ted an adverse impact on survival.
Since the first decade of the 2000s, an increasing number of
papers has been published on the adverse prognostic impact of
TDs in CRC. The meta- analysis by Nagtegaal et al. revealed an av-
erage 22% incidence of TDs (range, 5%– 42%) in a total of 10 106
patients in 17 studies, which variously included stages I– IV colon
or rectal cancer, depending on the study.9 The hazard ratio (HR)
on the prognostic magnitude of TDs was 2. 2 (1.6– 3.0) on disease-
free sur vival (DFS) (five studies, 1246 patients), 3.3 (2.2– 4.7) on
disease- specific survival (five studies, 4446 patients), and 2.9 (2.2–
3.8) on overall survival (OS) (three studies, 814 patients) in univar-
iate analyses. Importantly, the inclusion of additional variance did
not diminish the significance of the HR for TD even in the multi-
variable models.9
Goldstein and Turner repor ted that the presence of TDs is an in-
dependent poor prognostic factor and insisted that TDs are distinct
from LN metastases (LNM) and should not be considered their prog-
nostic equivalent.10 Actually, the background of the tumor is differ-
ent between patients with positive LNM and TD, where TD is more
likely to appear in advanced tumors, with a lower 5- year survival rate
in patient s positive for TD than LNM.11 However, the HR between
positive LNM and TD were not statistically different, demonstrating
4.1– 4.5 for LNM and 4.0– 5.3 for TD, respectively.11
3 | HISTOLOGICAL DEFINITIONS OF TDS
Varying terminology has been used in the literature to describe the
lesions associated with TDs, such as metastatic tumor nodules,6,7
extra- bowel skipped cancer infiltration,8 mesorectal microfoci,12
non- nodal metastatic foci,13 soft tissue implants of tumors,13 and
extramural discontinuous cancer spread.11 Over time, these terms
have gradually unified as TDs. However, the definition of TDs has
not yet been standardized effectively even in the UICC/American
Joint Committee on Cancer (AJCC) staging system, where patho-
logical definition of TDs has been changing at every revision from
TNM5 to TNM8 (Table 1). In its latest edition, some uncertainties
remained in TD definition, causing a diagnostic disparity of TDs, fol-
lowed by stage migration in a certain proportion of patients with
CRC (Table 2).
3.1 | Uncertainty in the diagnostic criteria for TDs
3.1.1 | Intravascular or perineural TDs
TDs exist in various forms but can pathologically be categorized into
two types, i.e., tumor nodules (ND) (Figure 2) and relatively small de-
posits of cancer predominantly confined to the vascular (lymphatic
or venous vessel) or perineural spaces (intravascular or perineural
TDs) (Figure 3). In 1997, TDs first appeared in TNM5 with the term
“tumor nodule,” which was also adopted by TNM6. The term “TDs
(satellites)” was alternatively used in TNM7, although without speci-
fied reason, in which TDs were defined as “macro- or microscopic
nests or nodules, in the lymph drainage area of a primary carcinoma
without histological evidence of residual LN in the nodule.” It is un-
clear whether TDs under TNM5, TNM6, and TNM7 included non-
nodular TDs, such as intravascular or perineural TDs (Figure 3) that
reportedly exist in approximately 3% in the peritumoral adipose tis-
sue located at >5 mm from the primary tumor and 1%– 2% in the “LN”
specimens (specimens postoperatively harvested for pathological
examination of LN metastasis).14
A single- center study focused on the distinction between nodu-
lar and intravascular TDs and revealed HRs of 4.7 (3.5– 6.2) and 2.5
(1.6– 3.8), respectively, and the AIC value for T staging was improved
when intravascular TDs were treated as T category.15 Additionally,
a multicenter study conducted by the Japanese Society for Cancer
of the Colon and Rectum (JSCCR), which included two cohorts com-
prising 1716 patient s and 2242 patients, respectively, revealed that
the statistic figures representing the performance of tumor staging
were improved when intravascular or perineural TDs were treated
as a T- factor.14
TNM7 and TNM 8 have provided a distin ction between p erineural
and lymphovascular invasions in terms of being treated as a T- factor
and V (venous invasion) or L (lymphatic invasion) classification, re-
spectively.16,17 However, the tumor stage, rather than V and L classi-
fication, is currently considered mostly as a treatment decision factor
in clinical practice; thus, we may better revisit the concept adopted

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UENO et al.
TABLE 1 Definition and categorization of tumor deposits (TDs) in staging systems
Staging system
(publication year) Terminology Definition Categorization criteria for tumor staging
TNM5 (1997) Tumor nodule A nodule in perirect al or
pericolic adipose tissue
without histological
evidence of a residual
lymph node in the nodule.
A tumor nodule of >3 mm in diameter is classified as regional
LNM; a tumor nodule up to 3 mm in diameter is classified in
the T category as a discontinuous extension, i.e., T3.
TNM6 (2002) Tumor nodule A tumor nodule in the pericolic
or perirectal adipose
tissue without histological
evidence of residual lymph
node in the nodule.
If the nodule has the form and smooth contour of a lymph
node, it is classified in the pN categor y as a regional LNM;
if the nodule has an irregular contour, it should be classified
in the T category and also coded as V1 (microscopic venous
invasion) or V2, if it was grossly evident, because there is a
strong likelihood that it represents venous invasion.
TNM7 (2009) Tumor deposit s
(satellites)
Macroscopic or microscopic
nests or nodules in the
pericolorectal adipose
tissue's lymph drainage
area of a primary
carcinoma without
histological evidence of
residual lymph node in the
nodule.
If tumor deposits are observed with lesions that would
otherwise be classified as T1 or T2, then the T
classification is not changed, but the nodule(s) is recorded
as N1c. If a nodule is considered by the pathologist as a
totally replaced lymph node (generally having a smooth
contour), it should be recorded as a positive lymph node
and not as a satellite, and each nodule should be separately
counted as a lymph node in the final pN determination.
TNM8 (2017) Tumor deposit s
(satellites)
Discrete macroscopic or
microscopic nodules of
cancer in the pericolorectal
adipose tissue's lymph
drainage area of a
primar y carcinoma that
are discontinuous from
the primary and without
histological evidence of
residual lymph node or
identifiable vascular or
neural structure.
If a vessel wall is identifiable on H&E, elastic, or other stains,
it should be classified as a venous invasion (V1/2) or
lymphatic invasion (L1). Similarly, the lesion should be
classified as a perineural invasion (Pn1) if neural structures
are identifiable.
The presence of tumor deposits does not change the primary
tumor T category but changes the node status (N) to pN1c
if all regional lymph nodes are negative on pathological
examination.
JSCCR8 (2013)
JSCCR9 (2018)
Extr amural cancer
deposits
without lymph
node structure
(EX)
Extramural cancer deposits
with no lymph node
struc ture within the
regional lymph node area.
EX includes localized
lesions comprising
lymphatic invasion, venous
invasion, perineural
invasion (vascular/
perineural invasion lesions),
and other lesions (tumor
nodule: [ND]).
All tumor deposits located
in the extramural f atty
tissue are regarded as
EX in tumors in which
continuous spread is
confined within the SM
or MP. Tumor deposits
located ≥5 mm from the
leading edge of the primary
tumor are designated as
EX for tumors that directly
penetrate the MP.
ND is treated as LNM and each ND is separately counted as
a lymph node in the final pN determination. Vascular/
perineural invasion lesions are treated as T- factor, thereby
changing the final pT determination (i.e., T3) in tumors that
would otherwise be classified as T1 or T2.
ND with his tological evidence of venous invasion or perineural
invasion in the nodule is recorded with a symbol of ND(V+)
or ND(Pn+) be cause it represents a strong likelihood of
getting a poor prognosis.
Abbreviation: EX, extramural cancer deposit without lymph node structure; H&E, hematoxylin and eosin staining; JSCCR , Japanese Society for
Cancer of the Colon and Rectum; LNM, lymph node metastasis; MP, muscularis propria; ND(Pn+), tumor nodule with histological evidence of
perineural invasion in the nodule; ND(V+), tumor nodule with histological evidence of venous invasion in the nodule; ND, tumor nodule without
histological evidence of residual lymph node structure; SM, submucosal layer.

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in TNM5 and TNM6 in which prognostic information of all TD types
was effectively reflected in either the T or N stage. In Japan, intra-
vascular or perineural TDs are treated differently from nodular TDs
in determining the tumor stage. Specifically, intravascular or perineu-
ral TDs are regarded as a T- factor, thereby making a tumor upstage
to pT3 if observed in otherwise pT1 or pT2 tumors. This may be com-
parable to the concept of the TD treatment adopted in TNM5 where
a pericolic or perirectal tumor nodule of up to 3 mm in diameter was
treated as a T category, i.e., a T3- determinant factor.5
3.1.2 | TDs with identifiable vascular or
neural structure
TD definition has increased in complexity in TNM7, which demands
pathologists to distinguish whether the origin of the TD is LNM or
not. Furthermore, the lesions with histological evidence of identifi-
able vascular or neural structure are not regarded as TDs by defini-
tion in TNM8. Conceivably, this is based on the concept that TDs
should only be applied to lesions having no identifiable origin,18 but
this is becoming a cause of st age migration (Figure 4). All isolated
tumor lesions in the mesocolon or mesorectum, including LNM, have
originated from migrated tumor cells that travel via the preexisting
anatomical structures, such as the lymphatic or venous systems, or
less frequently, the neural system, regardless of whether these are
pathologically evident or not. Differentiating the treatment of TDs
based on their assumed origin in the absence of clear evidence that
such pathological practice benefits patients in planning postopera-
tive treatment would not be logical.
Currently, approximately one in five patients with nodular TDs
also show signs of venous or perineural invasion in the nodule, and
such lesions have valuable prognostic information.11 The estimated
5- year survival rate of patients with such lesions was as low as 30%–
45% based on a single- center study and two cohorts in the JSCCR's
multicenter study.11,15 In Japan, since 2013, these no dules have been
recorded in pathological report s with the symbols ND(V+), ND(Pn+),
or ND(V&Pn+) and are incorporated in tumor staging, similar to
other nodular TDs.19
3.2 | What should be the distance of TDs from the
primary tumor?
Since TNM5, uncertainties were obser ved in the UICC/AJCC
definition concerning the area of peritumoral TD evaluation.
Specifically, the distance from the primary tumor or the bowel
wall for an isolated tumor lesion to be diagnosed as a TD has no
consensus.16,17 Approximately 16% of T3/T4 tumors have peritu-
moral deposits discontinuously located at >2 mm from the body
of the primary tumor and the muscularis propria. 20 TNM8 recom-
mended the lesions to be “discontinuous” from the primar y tumor
to be classified as TDs, but without specific criteria for judging
this “discontinuity,” resulting in a great deal of inconsistency in TD
diagnoses (Figure 5). Nagtegaal and Quirke brought up the dif-
ficulties that arise when determining whether a TD is a deposit
or just a continuous growth of tumor, causing TD misdiagnoses.21
Certainly, such a difficulty may well be understood in pathological
images of TDs used in some studies, in which the TD is so close
FIGURE 1 Area of adipose tissue harboring tumor deposit (TD). TDs exist in extramural adipose tissue attached to the bowel wall with
the primary tumor (A) and in a lump of adipose tissue postoperatively harvested for pathologic examination of LN metastasis (B). Regarding
the length of discontinuity to define peritumoral TD (two- headed arrow in [A]), a yardstick of 5- mm discontinuit y is used as a criterion for
judging a peritumoral TD in the Japanese classification of colorec tal, appendiceal, and anal carcinoma (third English edition), i.e., only a
deposit discontinuously located at ≥5 mm from the main body of the primar y tumor is attributed to the final pathological stage (see Figure 5).
LN, Lymph node; MP, Muscularis propria; TD, Tumor deposit
(A)
(B)

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UENO et al.
to the main body of the primary tumor that it is located within the
connective tissue extending directly from the primary tumor.22– 24
Since 2013, guidance for this issue was provided in the
Japanese Classification of Colorectal Carcinoma (8th Japanese
edition),25 wherein all deposits located in the extramural fatty tis-
sue are regarded as TDs in a tumor that is other wise diagnosed as
T1 or T2. A yardstick of 5 mm of discontinuity is used as a crite-
rion for judging a peritumoral TD for T3 or T4 tumors, i.e., only a
deposit discontinuously located ≥5 mm from the main body of the
primar y tumor can be attributed to the final pathological stage
(Figure 1). The 5- mm criterion for peritumoral deposits had been
arbitrarily determined based on the consensus of the committee
in the JSCCR , who emphasized the results of a multicenter study
in which the prognostic value of tumor stage had been improved
by the pre- planned assessment criteria for TDs, including the
5- mm criterion.11,14,26
Similarly, other pathologists attempted to make a yardstick for
the term “discontinuously.” For example, Gopal et al. determined
that at least 1 cm from the advancing edge was needed to diagnose
TDs.23 Conversely, Frankel and Jin considered the tumor nodule a
TD irresp ective of the dist ance of the tumor nod ule from the leading
edge of the tumor, when there is no clear connection and the nod-
ule appears discrete.27 However, this manner requires demanding
costly deeper sectioning to ascertain whether there is truly no con-
nection from the leading edge of the primary tumor body.
4 | TD CATEGORIZATION IN THE TNM
CLASSIFICATION
The TNM classification has categorized TDs based on the “size rule”
in TNM5, the “contour rule” in TNM6, and placed them into the “N1c
category” in TNM7 and TNM8. More specifically, a tumor nodule of
>3 mm is classified as the N category and up to 3 mm as the T cate-
gory in TNM5. The size rule might be introduced in the presumption
that the larger the TD was, the more likely that it originated in LNM,
although the rationale for the cut- off was not disclosed. In TNM6,
TDs were classified in the N category if the nodule had the form and
smooth contour of an LN.
Size or contour criteria are not presented in TNM7 or TNM8. TDs
were no longer treated as a T category,28 although there is a confusing
description in the 4th (2012)16 and 5th editions (2019)17 of the TNM
Supplement that discontinuous extramural extension becomes a rea-
son for a “pT3” diagno sis if there is regiona l LNM. TDs were classif ied as
N1c in tumors that would otherwise be classified as N0 in TNM7. The
number of TDs does not affect the N category although TDs should
TABLE 2 Issues to be solved for future international tumor staging systems regarding the definition and categorization of tumor
deposits (TDs)
Points at issue in the TNM8 Evidence to date associated with the issue
1. Uncertainty regarding the
definition of the “discontinuity” in
peritumoral TD diagnosis
1. There is no international consensus as to the definition of the distance from the advancing edge
of the main body of the primary tumor or bowel wall for peritumoral TD. Some criteria have been
proposed such as 1) ≥5 mm,11, 26 2) ≥1 cm,23 and 3) no clear connection.27
2. The “5- mm” is the only criterion for peritumoral TD that had been predetermined in a multicenter
st udy,11,26 and this criterion has been used across Japan since 2013.19
2. Uncer tainty regarding the
appropriateness of isolated
intravascular or perineural TDs
not being t aken into account in
tumor staging
1. Intravascular or perineural TDs have b een included in many studies to analyze the prognostic impact
of TDs and there is no evidence that the prognostic value of tumor st aging is improved by excluding
such lesions from staging factors.
2. The prognostic power of the T stage was improved by treating isolated intravascular/perineural
deposit s as a pT3- determining factor in tumors otherwise diagnosed as pT1 or pT2.14,15
3. Lack of meaningful rationale
of distinguishing TDs with
identifiable vascular or neural
struc tures from other TDs in
tumor staging
1. None of the studies that investigated the prognostic value of TDs have excluded TDs with
identif iable vascular or neural structure from the analyses and there is no evidence that the
prognos tic value of tumor staging is improved by excluding such TDs from staging factors.
2. Nodular TD accompanied by the finding of venous/perineural invasion in the nodule has a prognostic
value that is greater than other types of TDs.11,15
3. Impaired diagnostic reproducibility of tumor staging is inevitable due to interobserver disagreement
regarding the judgment for vascular or neural st ructure in the lesion. K appa statistic was rep ortedly
0.61 between nodular TD with venous/perineural invasion and other types of extramural
discontinuous lesion.11
4. Lack of evidence for the value of
the N1c categor y
1. A multicenter study showed that TNM7 adopting the N1c category is superior to TNM6
charac terized by the contour rule, but not to TNM5 characterized by the size rule in terms of its
prognostic power.26
2. Under the N1c rule, the tumor s tage does not change according to the number of existing TDs in the
resected specimens, but the number of TD has prognostic information.10,11,36,37
3. Impaired diagnostic reproducibility of tumor staging is inevitable due to interobserver disagreement
on the distinction between TDs and LNM. Kappa statistic was 0.74 between LNM and TDs,14 and
0.38 between “nodal” or “non- nodal” origin.18
4. An increasing number of studies indicate the value of a modified s taging system in which TDs are
counted individually same as lymph nodes in the f inal pN determination (see Ta bl e 3).
Abbreviations: CI, confidence interval; HR , hazard ratio; TD, tumor deposit.

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be separately counted and recorded in pathological reports.16,17 Also
in the TNM8 , the N1c category is used for all tumors with any T stage,
as long as all regional LNs are negative on pathological examination.
4.1 | Scientific evidence for TNM
classification revisions
After the publication of TNM6 that introduced the “contour rule,”
by which TDs were classified as LNM or venous invasion depend-
ing on whether the contour was smooth or irregular, the weak sci-
entific background in the process of revising the TNM system was
criticized.21 Already for TNM5 there were issues as the size rule
had been established based on a study that was not subsequently
published.29 Similarly, the contour rule was introduced into TNM6
based on three small studies,29 in which only 348,6 344,7 and 40 0
single- center patients10 were analyzed, respectively. None of
these studies were intended to assess the prognostic relevance
of TD in terms of it s shape, and only the prognostic impact of TDs
was repor ted according to their TD criteria. Quirke et al. ques-
tioned the validity of the TNM6 criteria for TDs because of the
contour rule.30
After the revision from the “size rule” to the “contour rule,” we
experienced further TNM classification system revisions, but the
process is not substantiated by any clear scientific evidence, thereby
inviting criticism that TNM should be restructured on a basis equiv-
alent to evidence- based guidelines.31
4.2 | TD categorization and its relevance to the
prognostic value of tumor staging
4.2.1 | Advantages and disadvantages of the
N1c category
The category of N1c was reportedly created to make a prognostic
subgroup for oncologist s who were in a quandar y about how to treat
patients who had TDs but lacked positive LN in terms of adjuvant
therapy administration.32 Additionally, the name of the category
“N1c” was selected because the letter c was the subsequent letter
in the alphabet and not necessarily to suggest prognosis.27 N1c is
repeatedly shown to not indicate poorer survival outcome than N1b
according to propensity score matching analyses on the Surveillan ce,
Epidemiology, and End Results (SEER) database.33,34
FIGURE 2 Tumor nodules in the pericolorectal adipose tissue lymph drainage area of a primary carcinoma. In TNM6, tumor nodules
without histological evidence of residual lymph node in the nodule are classified in the pN category as a regional lymph node metastasis
if the nodule has a smooth contour (A). A nodule with an irregular contour (B) is classified in the T category and also coded as V1 or V2.
In TNM7 and TNM8, tumor nodules are no longer treated as a T category. A nodule considered by the pathologist s as a totally replaced
lymph node is regarded as a positive lymph node, and otherwise, it may change the node status to pN1c depending on some conditions
defined differently in TNM7 and TNM8. No specific criteria for a nodule that should be diagnosed as a totally replaced lymph node are
being provided other than a short explanatory note that it is “generally having a smooth contour”. (A and B), hematoxylin and eosin staining;
Bar, 1 mm

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UENO et al.
Putting all evidence for the prognostic value of TDs into context,
a new category of N1c would be regarded as “partially” successful in
terms of prognostic stratification. Specifically, the TNM7 system has
successfully achieved its purpose because the evidence is suggesting
that N1c identifies a group of patients with poor survival outcomes,
thereby indicating the necessity of adjuvant therapy in patients with-
out LNM.35,36 Conversely, the current definition of N1c is an obsta-
cle in effectively utilizing the full prognostic information of individual
TDs. TDs are only affecting the tumor stage in patients with no pos-
itive LNs in the TNM system; furthermore, the number of TD is not
considered in deriving the final tumor stage. We can hardly agree that
the current TNM system successfully maximizes its performance of
prognostic prediction26 because of the substantial prognostic infor-
mation in the number of TDs regardless of LN positivity.10,11,36,37
4.2.2 | Tumor staging with the “counting” principle
In 2007, a first reported single- center study aimed to clarify
how TDs should be treated in tumor staging and revealed that N
FIGURE 3 Non- nodular type tumor
deposits in the pericolorectal adipose
tissue lymph drainage area of a primary
carcinoma. An intravascular tumor deposit
located near a non- met astatic lymph node
(A) and a perineural tumor deposit (B) in
the regional lymph node area. (A and B),
hematoxylin and eosin stain; Bar, 500 mm
FIGURE 4 Stage migration caused by different categorizations of a tumor deposit ( TD) depending on staging systems. The picture in the
upper- left panel indicates a peritumoral TD with a diameter of approximately 3.5 mm with an irregular contour and an identifiable vascular
structure. Under TNM5, this nodule is classified as an LN because it is >3 mm in diameter. On the contrary, this nodule is considered a lesion
of the T category because of its contour and is also coded as venous invasion under TNM6. The category N1c is used for this nodule in the
absence of regional LN metastasis under TNM7, whereas under TNM8, the tumor stage does not change by this nodule which is regarded
as venous invasion because the vascular structure is evident (arrow). Since 2013, this nodule has been invariably treated the same as LN
metast asis to derive the final N stage in Japan. Picture, hematoxylin and eosin staining; bar, 1 mm. The inset illustrates the magnification
of the part of the nodule that is indicated with an arrow (Victoria blue– hematoxylin and eosin staining). LN, Lymph node; MP, Muscularis
propria; TD: Tumor deposit

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staging was capable of more accurately predicting survival out-
comes than TNM5 or TNM6 when the number of nodular TD
was added to that of positive LN to derive the final pN stage ir-
respective of the size, contour, or estimated original structure (the
“counting” principle).15 The validity of the “counting” principle was
strongly validated in two multicenter cohorts in a study projec ted
by the JSCCR.26 An impor tant result obtained in the JSCCR study
was that increasing numbers of nodular TDs were associated with
adverse survival outcome. More importantly, statistic indexes for
tumor staging were in favor of a revised staging system based on
the “counting” principle compared to the TNM7 system in both N
and TNM stages.26
Recently, the prognostic value of the “counting” principle was
validated by an increasing number of studies (Table 3). Song et al.
analyzed 513 patients with CRC to compare the alternative staging
system based on the “counting” principle to the TNM7 system and
revealed the superiority of the “counting” principle in terms of prog-
nostic prediction.38 Similarly, the multicenter database of Lie et al.
with 4121 patients with stage II and III CRC revealed that the revised
pN categor y based on the “counting” principle was superior to the
TNM7 pN category for predicting DFS and OS.39 Additionally, two
reports from Pei et al. analyzed the SEER database of patients with
stage III CRC (21 290 patients treated between 1975 and 201640 and
9198 patients between 2010 and 201641 ), both of which demon-
strated that the “counting” principle improved the prognostic per-
formance of pN and TNM stages.
Two post hoc analyses of a phase III study for stage III colon can-
cer repor ted the value of the “counting” principle, the IDEA France
study (1942 patients)42 and the CALGB/SWAG 80702 study (2028
patients).43 The proportion of patients having TD was reported quite
differently as 10% in the IDEA France42 and 26% in the CALGB/
SWAG 0702,43 presumably due to variation in diagnostic criteria for
TDs between France and the United States and Canada. However,
the prognostic outcomes of patients who were restaged from pN1
to pN2 by the “counting” principle were similarly shown in two stud-
ies, i.e., their DFS rate was significantly lower than that of patients
confirmed with pN1 and was comparable to that of patients initially
staged as pN2.42,43 Additionally, Pyo et al. estimated the prognos-
tic power of modified staging based on the “counting” principle in
patients who completed 6 months of CAPOX treatment.44 Patients
upstaged to N2 from an initial stage of N1 experienced significantly
worse 3- year DFS compared to those remaining in the N1 stage (73%
vs. 89%), which was comparable to patients initially staged as N2.
A limited number of studies reported that the concept of the
N1c category could be reasonably accepted, ignoring the number
of TDs. A study from China concluded that the number of TDs was
not a prognostically significant parameter in the TNM staging sys-
tem because they found no difference in survival outcome between
patients having one TD and those with >1 TDs in any examined sub-
stage except for T3N1c.35 However, the number of patients included
in each substage was as small as only 3– 42. Some pathologists in
the United States have endorsed the current TNM staging system
and argued that the number of TDs should not be added to the total
number of positive LNs,27 but the evidence is lacking for this argu-
ment in terms of whether the current TNM sys tem truly achieves the
optimal prognostic grouping in patients with CRC.
FIGURE 5 The distance of peritumoral TDs to be located from the body of the primary tumor. The UICC defines tumor deposits ( TDs)
as discrete macroscopic or microscopic nodules of cancer in the pericolorectal adipose tissue's lymph drainage area of a primary carcinoma
that are discontinuous from the primar y, but the objective judgment is difficult for the discontinuity. (A) A nodule located at 7.5 mm from
the body of the primary tumor; (B) a nodule that is located just below the body of the primary tumor and some streaks of fibrous tissue
connecting them; (C) a nodule that is connected to the body of the primary tumor with cancerous tissue. In Japan, among these nodules,
only the nodule (A) is regarded as a TD that should be recorded and treated as an N factor according to the “5- mm” rule for the discontinuity
of TDs (Japanese classification of colorectal, Appendiceal, and anal carcinoma, third English edition). (A– C), hematoxylin and eosin staining;
Bar, 1 mm

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TABLE 3 Scientific literature reporting the value of new st aging based on the “counting” principle for categorizing tumor deposits (TDs) in colorectal cancer
Authors (publication
year) Study design Patients examined Summar y of the results
Ueno et al. (2007)15 Retrospective, single-
center study
1027 patients with T2– T4 CRC (1980– 1999) pNnew was superior to pNTNM5/TNM6 in AIC for CSS, when TDs other than
intravascular TD were added to the LNM count.
Ueno et al. (2012)26 Retrospective, multicenter
study
1716 (1994– 1998: first cohor t) and 2242 (1999– 20 03:
second cohort) patients with stage I– III CRC
pNnew and pTNMnew were superior to pNTNM5/TNM6/TNM7 and pTNNTNM7,
respec tively, in AIC and C- index for DSS, when nodular TDs were added to
the LNM count.
Song et al. (2012)38 Retrospective, single-
center study
513 patients with stage III CRC (1994– 2007 ) pNnew and pTNMnew were superior to pNTNM7 and pTNMTNM7, respectively, in
C- index for CSS, when TDs were added to the LNM count .
Li et al. (2016)39 Retrospective, multicenter
study
4121 patients with stage II and III CRC (200 4– 2011) pNnew was superior to pNTNM7 in C- index for DFS and OS, when TDs were
added to the LNM count.
Nagtegaal et al. (2017)9Systematic review and
meta- analysis
17 studies comprised 10 106 patients with CRC
(1964 – 2013)
An increasing number of TD was associated with poor outcomes. The
combination of TD and LNM was associated with a signific antly higher risk
of liver met astasis than LNM alone.
Delattre et al. (2020)42 Post hoc analysis of a
clinical trial
1942 patients with stage III colon cancer (2009– 2014) in
the IDEA France study
Patient s upstaged from pN1 to pN2new by the addition of TD to LNM count had
a significantly worse DFS than those with pN1new, and it was comparable to
pN2.
Pei et al. (2020)40 Retrospective database
analysis
21 290 patients with stage III CRC from the SEER database
(1975 to 2016)
pNnew and pTNMnew were superior to pNTNM8 and pTNMTNM8, respectively, in
AUC and AIC for OS, when TDs were added to the LNM count.
Pei et al. (2020)41 Retrospective database
analysis
9198 patients with stage III CRC from the SEER database
(2010– 2016)
pNnew was superior to pN in AUC and AIC for OS, when TDs were added to the
LNM count.
Cohen et al. (2021)43 Post hoc analysis of a
clinical trial
2028 patients with stage III CRC (2010– 2015) included in
the CALGB/SWOG 80702 study
Patient s upstaged from pN1 to pN2new by the addition of TD to LNM count
had significantly worse DFS and OS than those with pN1new, and they were
comparable to pN2.
Pyo et al. (2021)44 Retrospective, single-
center study
2446 patients with stage III CRC (2010– 2019) Among patients who completed 6 months of adjuvant chemotherapy, those
upstaged from pN1 to pN2new by the addition of TD to LNM count had a
significantly worse DFS than those pN1new, and it was comparable to pN2.
Abbreviations: AIC, Akaike's information criterion; AUC, area under the receiver- operating characteristic curve; C- index, Harrell's concordance index; CRC, colorectal cancer; CSS, cancer- specific
survival; DFS, disease- free survival; DSS, disease- specific survival; OS, overall survival; pNnew and pTNMnew, revised pN and pTNM based on the “counting” principle, respectively, i.e., a new method of
categorization with adding the number of tumor deposits (TDs) to the number of LNMs to derive a final N stage; pNTNM5/TNM6/TNM7, pN according to the definition of TNM5, TNM6, or TNM7; pTNMTNM7,
pTNM according to the definition of TNM7; SEER, Sur veillance, Epidemiology, and End Results.

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4.3 | Diagnostic reproducibility of tumor staging
Under the current UICC/AJCC definition for TNM staging, patholo-
gists have to distinguish a TD from some other isolated tumor lesions,
such as (1) an intravascular or perineural deposit, (2) a totally replaced
LN, and (3) a tumor nodule accompanied by venous or perineural inva-
sion, to derive the final TNM stage. Three multi- institutional studies
addressed the issue of judgment reproducibility of TDs. The JSCCR
study which involved 11 hospitals revealed a 0.74 kappa coef ficient
for distinguishing LNM from TDs and 0.51 for distinguishing between
smooth- contour nodules as a tot ally replaced LN and other types of
discontinuous lesions.14 Similarly, Brouwer et al. reported that the
kappa value for the distinction between “nodal” or “non- nodal” origin
was only 0.38 when evaluated by eight experienced gastrointestinal
pathologists.18 Rock et al. indicated that the complete agreement on
the distinction bet ween LNM and TDs was less than half under the
definition of the AJCC 7th edition even among pathologists with a
specific interest in gastrointestinal pathology.45 All these results high-
light the difficulties of achieving sufficient interobserver agreement in
distinguishing different types of discontinuous cancer spread lesions.
Consequently, at present, there is substantial interobserver inconsist-
ency in the tumor staging of individual patients caused by pathologi-
cal practice for TDs at the moment. The “counting” principle, wherein
an individual nodular TD is to be equally treated as positive LNs ir-
respective of the size, contour, or estimated original structure, would
be a promising, one- size- fits- all solution for this challenging situation.
5 | INTERNATIONAL CONSENSUS
NEEDED FOR FUTURE REVISIONS OF TNM
CLASSIFICATION
Uncertainty and confusion still remain regarding the role of TDs in
tumor staging as listed in Table 2. The definition of peritumoral TDs
in terms of the distance from the main tumor is an important issue,
and an international consensus on the definition of “discontinuity” for
TD is warranted. In Japan, the 5- mm criterion to define a peritumoral
TD is already employed across the country. The wide- ranging prac-
tices found among the literature also highlight the need for interna-
tional consensus on how to handle pathological specimens, such as
the number of sections needed for the diagnosis of TDs, how to count
the number of TDs, and whether to use immunohistochemical staining
as an adjunct of diagnostic tool. Furthermore, we have to accumulate
clinical data for establishing how we treat intravascular or perineural
TD, wherein t he lesions are less frequently observed than nodular TDs
but give a cer tain degree of prognostic information about the patient.
The UICC/AJCC has generated the definition and categorization
of TDs in the TNM staging system in which the origin of the TDs
plays a crucial part. However, no scientific evidence was presented
for the prognostic value of the origin of TDs. Furthermore, accurate
identification of the origin is impossible rather than challenging,46
and it is highly concerning that the diagnostic reproducibility of the
TNM classification is impaired due to the diagnostic inaccuracy of
TDs.18,30 Recent evidence suggests a promising solution, which is
to incorporate individual nodular TDs in the N staging based on the
“counting” principle. Certainly, we recognize the differences be-
tween TDs and LNM on some points, such as anatomical distribu-
tion, biological aggressiveness of the primary tumor, and prognostic
impact11; however, we have to bear in mind that the most import ant
role of tumor staging is, after all, accurate prognostic prediction.
In conclusion, the treatment of TDs in tumor staging should be
determined in terms of how it will maximize the prognostic value
of TNM classification and its reproducibility. All international initia-
tives to untangle the issues around TDs need to bring us to the op-
timal TNM staging by which patients would benefit from the most
evidence- based treatment. We should all aim for an evidence- based,
reproducible, and robust TNM staging system and considering our
suggestions should improve the current situation.
CONFLICT OF INTEREST
Hideki Ueno is a current Associate Editor of the Annals of
Gastroenterological Surgery.
ORCID
Hideki Ueno https://orcid.org/0000-0002-8600-1199
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How to cite this article: Ueno H, Nagtegaal ID, Quirke P,
Sugihara K, Ajioka Y. Tumor deposits in colorectal cancer:
Refining their definition in the TNM system. Ann
Gastroenterol Surg. 2023;7:225–235. https://doi.org/10.1002/
ags 3.12652