Annals of Oncology Advance Access originally published online on September 13, 2006
Annals of Oncology 2006 17(12):1803-1809; doi:10.1093/annonc/mdl312
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© 2006 European Society for Medical Oncology
gastrointestinal tumors |
Pathology practice patterns affect lymph node evaluation and outcome of colon cancer: a population-based study
1 Department of Research, Comprehensive Cancer Centre South, Eindhoven
2 Department of Public Health, Erasmus University Medical Centre, Rotterdam
3 Department of Pathology, Catharina Hospital, Eindhoven
4 Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
* Correspondence to: Mr V. E. Lemmens, Department of Research, Comprehensive Cancer Centre South, PO Box 231, 5600 AE Eindhoven, The Netherlands. Tel: 0031-40-2971616; Fax: 0031-40-2971610; E-mail: research{at}ikz.nl
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Abstract |
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Background: A large variation in the number of nodes examined between patients, hospitals, and regions has been reported for patients with colon cancer. We studied determinants of this variation and its relation to survival in the south of The Netherlands.
Patients and methods: All patients who underwent resection for stage I–III colon carcinoma diagnosed from 1999 to 2002 in the Eindhoven Cancer Registry area were included (n = 2168). Determinants of lymph node evaluation and their relationship to survival were assessed, including variation between the six departments of pathology.
Results: A median number of six lymph nodes per specimen had been examined. The median number for each department of pathology ranged from three to eight (P < 0.0001). After correction for relevant factors, this variation remained, resulting in differences in the proportion of N+ tumours between departments from 29% to 41% (P < 0.0001). The number of nodes examined was positively associated with survival. Survival for node-negative patients differed between the departments of pathology (up to hazard ratio 1.5; P = 0.02).
Conclusion: There was a large variation in lymph node evaluation between the departments of pathology, leading to differences in stage distribution and survival. Intervention strategies should be directed at nodal assessment.
Key words: colon cancer, lymph nodes, pathology practice, survival
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Colorectal cancer (CRC) is the second most common cause of cancer in industrialised countries [1, 2]. Yearly, >9200 patients are diagnosed with CRC in The Netherlands, 1300 of whom live in the area covered by the Eindhoven Cancer Registry [3]. Resection of the tumour with adequate margins and associated mesentery, including draining lymph nodes, remains the primary modality of treatment of CRC. Patients with positive lymph nodes may also benefit from adjuvant chemotherapy [4–8]. Therefore, lymph node analysis is one of the critical factors for therapeutic decision making. Several studies have described not only a positive association between the number of lymph nodes evaluated and prognosis for CRC patients but also a large variation in the number of lymph nodes examined between patients, departments of pathology, hospitals, regions, and countries [9–14]. This variation, which influences staging and subsequent therapy, may be explained by several mechanisms: first, the thoroughness of the surgical lymphadenectomy in order to remove all potential lymph node metastases; secondly, the extent and diligence of the pathologist's examination; and thirdly, inter-individual differences in the biological behaviour of the tumour and/or host, such as immune response, which may affect the number of traceable lymph nodes [11, 13]. In the current study of patients who had a colectomy for stage I–III [TanyNanyM0 (tumour–node–metastasis)] colon carcinoma, we determined the variation in lymph node examination and its relationship to stage distribution and survival in the Southern Netherlands, and the extent to which this variation could be attributed to local patterns in surgical and pathological practice or patient and tumour characteristics.
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patients and methods |
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data collection
The Comprehensive Cancer Centre South (Eindhoven Cancer Registry) covers a large part of the Southern Netherlands with
2.4 million inhabitants. This population-based registry is served by 10 hospitals, six departments of pathology, and two radiotherapy institutes. There are no university hospitals in the registry area. Between 6 and 18 months after diagnosis, the patients are registered by the trained administrators. The completeness of registration is estimated to be >95% [15]. All patients who had a colectomy for stage I–III [pTanyNanyM0 (pathological tumour–node–metastasis)] colon carcinoma in the 4-year period, 1999–2002, were selected from the database of the Eindhoven Cancer Registry (n = 2168). The patients' age at diagnosis, gender, and comorbidity according to a slightly modified version of the Charlson classification were recorded. Also, tumour site [right sided: colon ascendens (C18.0–C18.2) and colon transversum (C18.3–C18.5); left sided: colon descendens and sigmoid (C18.6–C18.9)], grade of tumour differentiation [low grade (well or moderately differentiated) versus high grade (poorly or undifferentiated tumours)], depth of invasion, and nodal involvement were recorded. Furthermore, the number of lymph nodes examined, adjuvant chemotherapy (yes versus no), hospital of surgery, and the department of pathology were registered. Socioeconomic status (SES) of the patient was defined at neighbourhood level (on the basis of postal code of residence area, 17 households on average) combining mean household income (in 1998) and mean value of the house/apartment (in 2000). The latter was derived from individual fiscal data made available at an aggregated level. Postal codes were assigned to one of three SES categories: low (1st–3rd decile), intermediate (4th–7th decile), and high (8th–10th decile).
Vital status of all patients on 1 January 2005 was assessed through the Central Bureau for Genealogy, where all deceased persons in The Netherlands are registered. Patients who had moved abroad (estimation <0.3%) were possibly incorrectly considered as being alive.
analyses
Differences between the departments of pathology according to the number of lymph nodes evaluated and the postoperative nodal status were tested by means of a 
2 test. The independent influence of pathology practice or patient and tumour characteristics on the number of lymph nodes evaluated was analysed by means of logistic regression analysis (LOGISTIC procedure). A Cochran–Armitage trend test was used to investigate whether there has been an increase or decrease in the number of nodes evaluated during the study period. To examine the hypothesis that the number of lymph nodes examined is related to survival, a multivariable proportional hazards regression analysis (PHREG procedure) was used to discriminate independent risk factors for death, stratified by nodal involvement. A model was built with and without the number of lymph nodes evaluated to investigate the hypothesis that the prognostic differences between the departments of pathology can be fully explained by the number of lymph nodes evaluated (after adjustment for age, gender, SES, the number of comorbid conditions, tumour site, tumour size, and adjuvant chemotherapy). Cases with missing values for any of the covariates were left out of the logistic and regression analyses. All statistical tests were two-sided. For all analyses, the SAS/STAT® statistical software (SAS system 8.2, SAS Institute, Cary, NC) was used.
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results |
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At the end of follow-up (1 January 2005), 1381 patients (64%) were alive.
The coverage of the six departments of pathology for the colon cancer resection specimens is depicted in Table 1. Three departments serve one hospital, while two departments cover three hospitals. All hospitals are community hospitals.
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The general characteristics of all 2168 patients are shown in Table 2. For 24% of patients, zero to three lymph nodes had been examined; for another 24% four to six nodes were examined versus seven to nine nodes for 16%, 10 or 11 lymph nodes for 6%, and
12 nodes for 13%.
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In Figure 1a and b, the numbers of lymph nodes evaluated among node-negative and node-positive patients are depicted. For all patients, the median number of lymph nodes examined was six (Table 3); for patients with pN0 and pN1/2 colon carcinoma it was five and six, respectively. The median number of lymph nodes examined in each department of pathology ranged from three to eight (P < 0.0001).
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In Table 4, the odds of having six or more nodes examined, as calculated by means of a multivariable logistic regression analysis, are listed. The number of lymph nodes examined clearly decreased with increasing age. Also patients with comorbidity were less likely to have had six or more lymph nodes examined. The chance was also lower for patients with left-sided tumours, as well as patients with pT1 tumours, male patients, and patients with nodal negative disease. There was a large variation between the departments of pathology; patients whose lymph nodes were evaluated in department No. 1 were 1.6 times more likely to have a minimum of six nodes examined compared with the reference department. Especially in departments No. 2 and No. 6, patients had a lower chance of having six or more nodes evaluated.
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Overall, there was no significant change in the number of lymph nodes evaluated from 1999 to 2002.
There was no difference in the number of lymph nodes examined between the hospitals covered by one and the same department of pathology. There was, however, a difference in the number of examined lymph nodes between the two pathology laboratories serving one and the same hospital: pathology department No. 3 examined a median of five nodes versus department No. 4 a median of eight nodes (P = 0.04) (resection specimens from the respective hospital only).
The postoperative stage distribution (pTNM) according to the department of pathology is depicted in Figure 2. In department No. 1, there was a relatively large proportion of T4 tumours (32%). The proportion of T2/T3N0 tumours varied from 43% in department No. 1 to 62% in department No. 2.
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The proportion of patients with lymph node metastases (pN1 or pN2; stage III) ranged from 29% in department No. 6 and 32% in department No. 2 to 41% in departments No. 1 and No. 5 (P < 0.0001) (Figure 3).
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After adjustment for relevant patient and tumour characteristics, the risk of death [hazard ratio (HR)] among node-negative patients differed between the departments of pathology, by up to HR 1.47 (Table 5). Inclusion of cases with a missing value for the covariate ‘number of nodes evaluated’ did not alter the variation between the departments. After adding the number of lymph nodes examined to the model, the differences between the reference department and the other departments became insignificant. The risk of death decreased clearly with increasing number of lymph nodes examined, for both patients with negative lymph nodes and patients with positive lymph nodes (to HR 0.56 and HR 0.68, respectively).
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discussion |
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The availability of increasingly effective postoperative chemotherapeutic agents for patients with nodal metastasis stresses the importance of lymph node analysis in colon carcinoma. In this population-based study in the Southern Netherlands, the median number of lymph nodes examined among patients who underwent resection for stage I–III (pTanyNanyM0) colon carcinoma was six. Other population-based studies reported median numbers of lymph nodes examined of seven to nine [9, 11, 16], while single-hospital studies reported median numbers up to 17 [17, 18]. A low number of lymph nodes evaluated in The Netherlands has already been reported by a Eurocare study among patients diagnosed in 1990, covering 11 European cancer registries [10]. The Dutch registries had the smallest proportion of patients with
12 lymph nodes examined: 5% in the Dutch Eindhoven Cancer Registry and 2% in the Dutch Rotterdam Cancer Registry. In a large USA population-based study, geographic location was an important predictor of adequate lymph node evaluation, indicating that surgical and pathological practices probably play an important role [11]. This was recently confirmed by a Swedish population-based study, where the median number of lymph nodes examined varied from 6 to 12 between the seven departments of pathology [9]. Also in the current study, there was a large variation between the departments of pathology. The absence of a difference in the number of lymph nodes evaluated between the hospitals covered by one and the same department of pathology indicated that pathology practice patterns probably played a more important role than surgical practice patterns. The significance of the variation in pathology practice is emphasised by the differences in nodal status and survival between the departments of pathology. In addition to different degrees of diligence, the technique used by the pathologist can influence lymph node assessment. A single-hospital study reported a mean number of >20 lymph nodes evaluated with standard manual dissection methods of pathology evaluation, without clearing solutions or ancillary techniques [17]. An example of a straightforward way of improving adequacy of nodal harvest is a longer duration of specimen fixation. This may significantly upstage colon carcinoma from node-negative to node-positive after an additional 24-h fixation in formaldehyde before specimen dissection [19, 20]. Furthermore, with respect to the limited resources of pathology, sentinel node detection of the first draining node might be one of the key techniques to allow the pathologist focusing to nodes at risk. The Dutch CRC treatment guidelines, in agreement with the American Joint Committee on Cancer and the Tumour, Node, Metastasis Committee of the International Union Against Cancer, require a minimum of 12 nodes to be examined for adequate staging [21]. However, this threshold of at least 12 nodes is not universally accepted. The recommendation of the Royal College of Pathologists in the UK is that all lymph nodes identified in the resection specimen should be examined histologically but does not specify an arbitrary minimum number since it is recognised that the number of lymph nodes identifiable in a specimen varies according to several factors, as indicated also by the results of this and other studies [20, 22–25].
The number of lymph nodes evaluated may also be related to the immune response of the patient; size and morphology of lymph nodes are modified by immune responses against neoplastic cell products [13, 25, 26]. Older patients probably have a diminished immune response, which would explain the effect of age on the number of lymph nodes examined in this and other studies [11, 13, 27]. However, since the immune response is expected to be evenly distributed geographically among patients with colon cancer (especially after adjustment for age and other possible relevant factors), this does not explain the variation between the departments of pathology. In agreement with previous studies, we also found an effect of gender on the adequacy of node evaluation [11, 13]. The observation that a larger number of lymph nodes was examined with more advanced stage of disease can partly be explained by the fact that retrieval of a higher number of nodes logically increases the possibility that existing positive lymph nodes will be detected. Furthermore, positive lymph nodes are generally slightly larger than negative lymph nodes, thus being more likely to be detected [18, 28]. The presence of an inflammation surrounding the tumour in patients with T3 or T4 tumours, with subsequent enlargement of the draining lymph nodes, explains the increased likelihood of an adequate lymph node evaluation among patients with stage II (pT3/4) disease compared with stage I (pT1/2) [11]. Another explanation may be a more thorough search by the surgeon or pathologist when a larger penetrating tumour is present. Our finding that patients with right-sided colon cancer had more lymph nodes evaluated is consistent with other studies and not unexpected, since larger amounts of mesentery are often found in right-sided resections and subtotal colectomy [13, 27, 29]. However, the absence of a difference in the number of lymph nodes examined between the hospitals which were covered by the same department of pathology indicates that pathological rather than surgical practice patterns are responsible for the observed variation in lymph node evaluation, strengthened by the observation that there was a difference in the number of nodes examined between the two pathology departments serving one and the same hospital. The commitment of the pathologist and the availability of resources are likely to be important factors in explaining this variation between the departments of pathology. In a Canadian study, reinforcing strategies aimed at surgeons and pathologists, including the use of a pathology reporting template, increased the median number of lymph nodes evaluated from 8 to 18, in a 30-month period [30].
The current study also revealed differences in depth of tumour invasion between the departments of pathology, with one department showing a significant higher proportion of T4 tumours. An explanation for this might be the significantly larger proportion of patients with a low SES presenting in that hospital; possibly these individuals postpone seeking medical help after being confronted with unexplained symptoms.
Our results confirmed the strong prognostic influence of an adequate lymph node examination, which may partly be related to the intensity of the patient's immune response [9–14, 31, 32]. After adjustment for relevant factors, such as stage and adjuvant therapy—but not the number of lymph nodes examined—there was a variation in patient survival between the departments of pathology. Among node-negative patients, the departments of pathology with the lowest median number of examined nodes yielded the worst patient survival, reflecting that this group of node-negative patients contained N1 patients wrongly staged as N0. Inclusion of the number of lymph nodes examined decreased the differences between the departments. This means that a reduction in mortality among these node-negative patients could be achieved by increasing the number of lymph nodes examined in the departments with the lowest numbers. The difference in survival among node-positive patients after adjustment for the number of nodes examined indicated that other relevant clinical features differ between institutions, in addition to the determinants we assessed in our analyses. For example, the surgical technique, the completeness of the resection, and the experience of the surgeon all may have a prognostic influence [33, 34]. In a previous study, we have shown that the proportion of elderly patients with stage III colon cancer in the south of The Netherlands treated with adjuvant chemotherapy varied by institution, and was furthermore affected by age, comorbidity, gender, and SES [35]. We have adjusted for this variation in the analyses of the present study; however, appropriate adjuvant treatment decisions and adequate lymph node evaluation obviously go hand in hand. The results of the present study do not ground the administration of adjuvant chemotherapy to node-negative patients who did not have an adequate lymph node evaluation. The effectiveness of adjuvant chemotherapy in this group of patients has yet to be confirmed in large clinical trials.
In conclusion, we demonstrated a low number of lymph nodes examined among patients with colon cancer in the south of The Netherlands, with a large variation between the departments of pathology leading to differences in stage distribution and prognosis. This finding becomes more relevant with more frequent use of new, increasingly effective chemotherapeutic agents. In the future, lymphatic mapping might lead to inclusion of all tumour-draining lymph nodes and molecular tumour markers may provide diagnostic information that would preclude assessment of regional lymph nodes [36–39]. Until then, therapeutic decisions will be on the basis of lymph node analysis, and intervention strategies should be directed at nodal assessment.
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The authors would like to thank the registration team of the Eindhoven Cancer Registry for their dedicated data collection.
Received for publication April 12, 2006. Revision received July 18, 2006. Accepted for publication July 19, 2006.
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