Download The Relationship between Involved Lymph Nodes, Metastatic Nest

ORIGINAL PAPER
The Relationship between Involved Lymph Nodes, Metastatic
Nest Diameters and Prognosis in Colorectal Cancer
Fariborz Mokarian¹, Mohammad Hossein Sanei², Ali Chehrei², Victoria Nurozi3, Ali Akbar Nurozi3
1) Department of Oncology; 2) Department of Pathology; 3) Intern, Medical Faculty, Isfahan University of Medical
Sciences, Isfahan, Iran.
Abstract
Introduction. Several studies evaluated the relation
between colorectal cancer prognosis and various factors
such as: depth of tumor invasion, involved lymph nodes size,
counts and locations, metastatic nest expansion. We assessed
the prognostic significance of the ratio between metastatic
nest and involved lymph node diameter in colorectal cancer
cases. Methods. A historical cohort study was conducted
on patients with known colorectal cancer and metastatic
lymph nodes (Astler Coller’s stage C), in whom diagnosis
was confirmed at least one year before the study. Less than
two months following surgery, patients were treated with the
same chemotherapy protocol. Metastatic lymph node sizes
were recorded in 63 pathologic samples. Metastatic nest
borders were marked using a marker and a 40x magnifying
microscope. The greatest metastatic nest to involved lymph
node diameter ratio was obtained. The data were analyzed
with SPSS analytic software. Actuarial and Kaplan-Meier
methods were used to estimate survival. Survival functions
were compared by Log rank and Cox regression tests.
Results. There was no significant relation between colorectal
cancer prognosis and: the greatest involved lymph node
diameter, the metastatic nest diameter and the ratio metastatic
nest to involved lymph node diameter (p-values in sequence:
0.1, 0.07, 0.2). Conclusion. We found no significant
relationship between the colorectal cancer prognosis and the
greatest lymph node diameter, the greatest metastatic nest
diameter and the greatest metastatic nest to involved lymph
node diameter ratio. Further studies are required in order to
reach a decisive conclusion.
Keywords
Colorectal cancer – metastatic nest – lymph node size
– prognosis.
Received: 14.12.2007 Accepted: 20.05.2008
J Gastrointestin Liver Dis
September 2008 Vol.17 No 3, 305-308
Address for correspondence:
Mohammad Hossein Sanei
Isfahan University, Medical Faculty
Pathology Department, Isfahan, Iran
E-mail:[email protected]
Introduction
Nowadays, colorectal cancer is the third cause of
mortality due to carcinoma worldwide [1]. According to one
study performed in our country (1996-2000), age adjusted
incidence rate in men and women with colorectal cancer was
8.2% and 7% in 100,000, as the third and fourth common
cancer in each gender, respectively [2]. Staging is the most
significant factor to select supplement therapy measures
following tumor resection. Based on TNM staging the most
important factors which influence prognosis are local tumor
extension, lymph node involvement and distance metastasis
[3, 4].
Prognosis is heterogeneous among patients having lymph
node involvement [5, 6]. Several attempts have been made
to subclassify metastatic lymph nodes and these have led to
dividing N in the TNM staging system into two subgroups,
N1 (1 to 3 involved nodes) or N2 (4 or more involved nodes)
[7]. On the other hand, some recent studies have evaluated
the prognostic significance of lymph node size in patients
with esophageal and gastric cancers [8, 9].
There are a few controversial studies regarding the role of
metastatic lymph node size on prognosis [10, 11]. However,
further studies are required in order to evaluate this criterion
of metastatic lymph node sub-classifying.
To have a more accurate staging and improvement in
patient treatment and survival, we conducted a study on the
relation between colorectal cancer prognosis and metastatic
nest with involved lymph node diameter ratio.
Materials and method
This study is a historical cohort one. The samples are
65 known cases of colorectal cancer with metastatic lymph
nodes Astler Coller’s stage C hospitalized in the Alzahra
hospital, in whom diagnosis had been confirmed at least
1 year before the beginning of our study. In less than two
months following surgery, they had been treated with the
same chemotherapy protocol, based on 5-FU. Those with an
additional carcinoma or metastasis were excluded.
All patients who had the eligibility criteria during 1996-
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Mokarian et al
2005 in Alzahra hospital were selected. None of the rectal
cases had received preoperative radiotherapy. Then in March
2007, their survival rates were calculated. We looked at their
files available in Alzahra hospital to gather data, to record
the pathology sample number and their phone number for
following them up. In order to confirm the diagnosis, to
obtain the number and size of involved lymph nodes and
the greatest metastatic nest to lymph node diameter ratio,
all the pathologic samples were reviewed.
Metastatic lymph node diameter was measured and
the metastatic nest was marked with a marker and a 40x
magnifying microscope. Its size was measured by using
a standard ruler, too. Finally, the greatest metastatic nest
to involved lymph node diameter ratio was obtained. All
the samples were checked by two pathologists. The data
was analyzed with SPSS analytic software. Actuarial and
Kaplan-Meier methods were used to estimate the survival.
Survival functions were compared by using the Log rank
and Cox regression tests.
Results
One hundred and sixty nine known cases of colorectal
cancer during 1996-2005 were evaluated. Sixty three
patients in Astler Coller’s stage C who had received the
same adjuvant chemotherapy based on 5-FU in less than two
months following surgery entered this study. From these 63
cases, 28 patients (44.4%) were females. The mean age of
patients was 62.53 years (59.09-65.97). The mean count of
recovered lymph nodes was 4.45 (CI: 3.7-5.1). Thirty-four
patients (54%) had died up to March 2007 and 29 (46%)
were still alive.
In Table I survival analysis data are listed. The patients’
survival median was 43 months.
By using the ROC curve analysis, none of the variants
such as lymph node counts, the greatest lymph node diameter,
and the greatest metastatic nest diameter was appropriate in
predicting death.
For the greatest metastatic nest to lymph node diameter
ratio, the ROC curve analysis was also used. Its AUC was
0.57; therefore this variant does not seem to be appropriate
in predicting death.
Considering ROC analysis, the best cut off point was
0.73 for the metastatic nest to lymph node diameter ratio.
The survival mean was 40.97 months (31.08-50.85) for the
group with metastatic nest to lymph node diameter ratio
below 0.73, while for the group above 0.73, it was 59.5
months (39.0-80.0). So, in the log rank test results, there was
no statistical difference (p=0.13) (Fig. 1). In addition, there
was no significant difference in survival between lowest and
higest cut off values.
With regard to ROC analysis, the best cut off point was
4.5 mm for the greatest metastatic nest size. Survival mean
was 38.68 months (32.65-44.70) for the group with the
greatest metastatic nest size below 4.5, while for the group
above 4.5 mm it was 54.98 months (39.07-70.89). Thus, the
log rank test results showed no statistical difference (p=0.9).
There was also not a significant difference in survival
between lowest and highest cut off values.
Considering ROC analysis, the best cut off point was 6
mm for the greatest nodal size. Survival mean was 41.07
months (34.52-47.62) for the group with the greatest
metastatic nest size below 6 mm, while for the group above
6 mm it was 54.73 months (38.33-71.14). There was no
statistical difference according to the Log rank test results
(p=0.7).
The Cox-Regression analysis showed that only age
was an independent prognostic factor (p <0.01, Odds Ratio
0.96). Other variables such as greatest nodal size, greatest
metastatic nest size and metastatic nest to lymph node
diameter ratio were excluded in our model.
Fig 1. Survival functions according to metastatic nest to lymph
node size ratio (Kaplan-Meyer).
Table I. Survival analysis in colorectal cancer studied cases
Time interval
(year)
Entered cases
count
Censored cases
count
Mortality count
per interval
Survival rate
per interval
Cumulative
survival
Standard
Error
Hazardous rate
per interval
Standard
Error
0-1
63
1-2
57
0
6
0.90
9
11
0.79
0.90
0.03
0.0083
0.0034
0.72
09.05
0.0195
0.0058
2-3
3-4
37
9
9
19
5
2
0.72
0.52
0.07
0.0268
0.0088
0.87
0.46
0.07
0.0108
4-5
12
3
0.0076
3
0.71
0.32
0.08
0.278
0.0158
5-6
6
2
1
0.80
0.26
0.08
0.0185
0.0184
>6
3
1
2
0.20
0.05
0.06
-
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Lymph nodes, metastatic nest diameters and prognosis in colorectal cancer
Discussion
For the colorectal cancer prognosis, regional lymph node
involvement is a significant factor. Several random studies
have shown that patients in TNM III stage (with lymph
node involvement) may require supplement therapies [12,
13]. This group of patients is a heterogeneous population
with a variable 5 year survival ranging from 22% to 66%
[13, 14].
The aim of this study was to evaluate the relationship
between colorectal cancer prognosis and metastatic nest to
involved lymph node diameter ratio. According to our results
in known cases of Astler Coller’s stage C colorectal cancer
which had been treated by the same chemotherapy protocol
based on 5-FU in the first two months following surgery,
the lymph node diameter, the metastatic nest diameter of
involved lymph nodes and metastatic nest to involved lymph
node diameter ratio have no role in the survival outcome.
Rodrigues-Bigas et al have evaluated the relationship
between the involved lymph node size and prognosis. They
studied 77 patients in Duke’s C stage and considered the
size of 5 mm as a cut point, then divided the patients into
two groups. They did not find any significant difference in
overall survival and disease free survival between the two
groups [11]. Our findings are similar to their results.
Dhar et al evaluated 107 patients with Duke’s C stage
in a prospective study. They measured the diameter of the
largest metastatic lymph node and assessed the cut point and
prognosis. There was a significant difference in the survival
of patients which had metastatic lymph node size ≤9 mm and
those with size ≥ 10 mm. They proposed sub-classification
of metastatic lymph node based on size to n1 ≤9 mm and
n2 ≥ 10 mm [10].
In another study it was showed that the sizes of metastatic
lymph nodes were significantly larger than of the free ones
[15].
Our findings and those of Rodrigues-Bigas et al are
similar, but they differ from the study of Dhar et al [9].
There are two differences in our methods: their study was
prospective and they studied more patients. However, we
evaluated both metastatic nest diameter and metastatic nest
to involved lymph node diameter ratio.
One limitation of our study was the low mean recovery
of lymph nodes. The minimum of lymph node recovery
suggested for considering a patient as lymph node free is 14
or 15, but all our cases had lymph node involvement and had
taken adjuvant chemotherapy (stage III) [16,17]. Whether
a higher number of lymph nodes could have influenced
our study remains undecided. The only possibility was to
recover a larger involved lymph node which contained a
larger metastatic nest. Practically, this possibility is less
likely, because when a pathologist is searching for rapid
lymph node recovery, he or she will find large lymph nodes
usually more than 7 mm. The time consuming part of work
is searching for small lymph nodes which may be missed.
Therefore, it seems that this limitation did not significantly
influence our study.
307
Conclusion
We found no significant relationship between colorectal
cancer prognosis and the greatest lymph node diameter, the
greatest metastatic nest diameter, the greatest metastatic
nest to involved lymph node diameter ratio, but considering
the controversies existing among different studies, further
research and meta-analytic studies based on the existing data
are required for a decisive conclusion.
Conflicts of interest
None to declare.
References
1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol
2001; 2: 533–543.
2. Ansari R, Mahdavinia M, Sadjadi A, Nouraie M, Kamangar F,
Bishehsari F, et al. Incidence and age distribution of colorectal
cancercolorectal cancer in Iran: Rresults of a population-based cancer
registry. Cancer Lett 2005; 240: 143-5147.
3. Beahrs OH. sStaging of cancer of the colon and rectum. Cancer 1992;
70 (5 Suppl): 1393-1396.
4. Hutter RVP, Sobin LH. A universal staging system for cancer of
colon and rectum. Let there be light. Arch Pathol Lab Med 1986;
110: 367-368.
5. Merkel S, Mansmann U, Papadopoulos T, Wittenkind C,
Hohenberger W, Hermanek P. The prognostic in homogeneity of
colorectal carcinomas Stage III: a proposal for subdivision of Stage
III. Cancer 2001; 92: 2754–2759.
6. Greene FL, Stewart AK, Norton HJ. A new TNM staging strategy for
node-positive (stage III) colon cancer: an analysis of 50,042 patients.
Ann Surg 2002; 236: 416–421.
7. Sobin LH, Wittenkind C, eds. UICC/AJCC TNM classification of
malignant tumors. 6th edit , NewYork: JonWiley and Sons; 2002.
8. Dhar DK, Tachibana M, Kinukawa N, et al. The prognostic
significance of lymph node size in patients with squamous esophageal
cancer. Ann Surg Oncol 2002; 9: 1010–1016.
9. Dhar DK, Kubota H, Kinukawa N, et al. Prognostic significance of
metastatic lymph node size in patients with gastric cancer. Br J Surg
2003; 90: 1522–1530.
10. Dhar DK, Yoshimura H, Kinukawa N, Maruyama R, Tachibana
M, Kohno H, et al. Metastatic lymph node size and colorectal
cancercolorectal cancer prognosis. J Am Coll Surg 2000; 200: 2028.
11. Rodriguez-Bigas MA, Maamoun S, Weber TK, Penetrante RB,
Blumenson LE, Petrelli NJ. Clinical significance of colorectal
cancercolorectal cancer: metastases in lymph nodes < 5 mm in size.
Ann Surg Oncol 1996; 3: 124-130.
12. Compton CC, Fenoglio-Preiser CM, Pettigrew N, Fielding LP.
American Joint Committee on Cancer Prognostic Factors Consensus
Conference: Colorectal Working Group. Cancer 2000; 88:17391757.
13. Dukes CE. Histologic grading of rectal carcinoma. Proc Royal Soc
Med 1937; 30: 371-376.
14. Jass JR, Love SB, Northorer JMA. A new prognostic classification
of rectal cancer. The Lancet 1987; 1: 1303-1306.
15. Csemi Cserni G, Tarjan M, Bori R. Distance of lymph nodes from
the tumor: an important feature in colorectal cancercolorectal cancer
specimens. Arch Pathol Lab Med 2001; 125: 246-249.
308
16. Goldstein NS. Lymph node recoveries from 2427 pT3 colorectal
resection specimens spanning 45 years: recommendations for a
minimum number of recovered lymph nodes based on predictive
probabilities. Am J Surg Pathol 2002; 26: 179-189.
Mokarian et al
17. Wong JH, Severino R, Honnebier MB, Tom P, Namiki TS. Number
of nodes examined and staging accuracy in colorectal carcinoma. J
Clin Oncol 1999; 17: 2896-2900.