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The sentinel node (SN) in colorectal cancer

Prof R.A.E.M. Tollenaar Dr W. Kelder

The SN in colorectal cancer- overview of presentation
• • • • • • TNM staging – lymph node staging in colorectal cancer Sentinel node technique – general overview Lymph node drainage patterns in colon and rectal cancer Sentinel node technique in colon and rectal cancer Benefits and drawbacks of the SN procedure Conclusions

Colorectal cancer – TNM and prognosis
pTNM T1-2 N0 M0 T3-4 N0 M0 T1-4 N1-2 M0 -T1-2 N1 M0 -T3-4 N1 M0 -T ? N2 M0 T1-4 N1-2 M1 Stage (AJCC) I II III IIIa IIIb IIIc IV 5-year survival rate (%) 90 80 50 60 42 27 5

TNM stage and prognosis
• 20 % of stage II patients will develop recurrence in spite of an apparently evident surgical cure Causes?
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Patient factors Tumour biology (angio-invasion, grade, type of tumor, gene-expression profile) Quality of the surgical resection Quality of the pathological examination

Adjuvant chemotherapy is reserved for stage III patients and some, high risk stage II patients

Quality of the surgical resection vs prognosis
• Influence of • Tissue handling • No-touch technique (Turnbull Ann Surg 1967 Wiggers Br J Surg 1988) • Low or high tie of vascular pedicles • R0 vs R1/2 resection Training of surgeons leads to better results
(Dutch and Swedisch TME trials: Kapiteijn NEJM 2001, Birgisson EJSO 2005, Pahlman ECCO 2007)

Quality of the pathological examination vs prognosis
• Guidelines – standardized pathology report – at least 12 lymph nodes Number of lymph nodes*

Recurrence rate and survival rates are related to the number of examined lymph nodes It is not known exactly how many lymph nodes have to be examined, numbers vary from 8, 12, 18 to an unlimited number In 75% of cases less than the recommended 12 nodes are examined


(Law et al JSO 2003, Le Voyer JCO 2003, TepperJCO 2001, Wong Dis Colon Rectum 2002, Wright AnnSurg Oncol 2003, Goldstein AM J Surg Path 2002, Kelder Dis Colon Rectum 2008)

Pathological examination – standard technique
• • • Fixation in 10% buffered formalin (1 night) Lymph node retrieval by palpation and visualization One section if node<0.5 cm, 2 sections if node 0.5-1,0 cm Node >1.0 cm sections at 0.3 cm intervals

Pitfalls: • Less than 1% of the node is examined • 70% of the metastases are found in nodes < 5 mm

Methods to improve lymph node staging
• Retrieval of more nodes • Fat-clearance more than 50 nodes per specimen
(Scott et al Dis Colon Rectum 1994, Haboubi et al Int J Colorectal Dis 1998)

Fixation method (Kelder et al EJSO 2007)

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Multiple level sectioning: 15-20% upstaging (Diest et al, Sem Surg Onc 2001) Immunohistochemistry: 10-76% upstaging (Feezor et al Ann Surg Onc 2002) PCR 46-54% upstaging (Liefers N Eng J Med 1998, Bilchik JCO 2001, Hayashi Lancet 1995)

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Labour intensive and costly What is the prognostic value of a micrometastasis


Lymph node sampling - micrometastases

Iddings et al Ann Surg Oncol 2006 – meta-analysis • Retrospective molecular detection of metastases by RT-PCR shows an adverse effect on survival in stage II patients IHC detected micrometastases do not have a significant effect on survival (there is a survival difference, no significance due to heterogeneity in studies)

Lymph node staging

With a minimal number of 12 nodes, the pathologist probably only takes a sample of the lymph node basin We need the best possible sample

Sentinel lymph node (SN)

Sentinel node: The first lymph node with the most direct drainage from a tumor site which has the highest potential to contain metastases when present*

*Morton et al, Arch surg 2002

SN procedure - history
• • 1923 Braithwaite – lymphatic flow from ileocecal valve with indigocarmine 1950 Weinberg - lymphatic mapping with pontine sky blue to identify the thoracic duct and lymph nodes in gastric and pulmonary cancer 1960 Gould – SN in parotid carcinoma 1977 Cabañas – SN procedure in penile cancer 1992 Morton - SN procedure in melanoma with patent blue 1994 Giuliano – SN procedure in breast cancer

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Sentinel node – clinical implications
• Melanoma and breast cancer
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Easy access for injection of blue dye and/or radio-active colloid Prevention of an unnecessary lymphadenectomy when negative SN Positive SN lymphadenectomy in 2nd stage Nodal upstaging by the detection of micrometastases through the use of ultrastaging techniques on the SN

Colorectal cancer
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Access less easy No indication for limited dissection – one stage procedure is preferred Nodal upstaging through ultrastaging techniques on the SN Detection of aberrant lymphatic drainage patterns, leading to an adjustment of the initial resection

Sentinel node – colorectal lymphatic drainage

Lange J.F. – Surgical anatomy of the Abdomen – ISBN 9035225082

Sentinel node – colorectal lymphatic drainage

Distribution of sentinel nodes in colorectal cancer (Kitagawa

Dis Col Rectum 2002)

Sentinel node – rectal lymphatic drainage
• • Difference between upper and lower rectum (middle Houston’s valve) Upper rectum: predominantly upward drainage associated with the inferior mesenteric artery – similar to colon TME Lower rectum: lateral lymphatic channels along the lateral ligament (middle rectal artery) towards the lateral pelvic and internal iliac nodes Japan: lateral pelvic lymphadenectomy in patients with T3/4 cancers below the peritoneal reflection

Rectal cancer – lateral node involvement

Risk factors: involved mesorectal nodes, female sex, advanced T-stage, lymphovascular invasion
Yano Br J Surg 2008

Rectum – lateral lymphadenectomy

Sentinel node in colorectal cancer– technique
Technique – in vivo or ex vivo
• Injection of 1-2 ml blue dye / radioactive colloid subserosally in 4 quadrants around the tumour or: Injection of blue dye / radioactive colloid submucosally through endoscope Mobilization of colon before injection only if necessary Marking of SN with sutures within 5 minutes If SN outside of planned resection area, excise separately or extend resection

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Sentinel node – technique

Sentinel node – technique

Sentinel node – technique

Sentinel node – technique / results
SN colon cancer in experienced hands*
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Success rates 92-94% Sensitivity 89-94 % Negative predictive value 93-94%

Meta-analysis 2007 (world J surg 2007, des guetz et al)
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182 studies SN in colorectal cancer, 48 prospective, 33 in review 1794 patients Success rate 90%, sensitivity 70%, specificity 81% Heterogeneity of trials, one group (Saha/Bilchik) shows better results Importance of learning curve and patient selection

* (Bembenek Ann Surg 2007, Bilchik Arch Surg 2006, Saha Am J Surg 2006, Kelder/Braat Int J colorectal dis 2007, Kitagawa Dis Col Rectum 2002, Saha Ann Surg Oncol 2001)

Sentinel node – technique / results
• SN in colorectal cancer – failures*
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Advanced tumour stage with overt nodal disease – skip metastases Previous colorectal surgery High body mass index of patients More than one tumour Long interval between injection of dye and SN detection Too many surgeons performing few procedures Preoperative (chemo)-radiation – rectal cancer

*Joosten Br J Surg 1999, Bertagnolli Ann Surg 2004, Read Dis Col Rectum 2005, Bembenek Surgery 2004, Braat Br J Surg 2005

Sentinel node – rectal cancer
• Very interesting regarding lateral lymphatic drainage, however*:
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Rectum: infraperitoneal location, bulky mesentery (submucosal injection) Pathologist: intact mesorectum to detect the circumferential margin Pre-operative (chemo) radiation alters lymphatic flow by obliteration of lymphatic channels

Possible solutions: • No pre-operative (chemo) radiation – no option in the Netherlands • Use of radio active colloid and SN retrieval by pathologist after surgery

*Kitagawa Dis Col Rectum 2002, Saha Ann Surg Oncol 2001, Bilchik eur J Cancer 2002, Bembenek Surgery 2004, Braat Br J Surg 2005

Sentinel node – rectal cancer - results
• Japan (Kitagawa Dis Col Rectum 2002)
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No pre-operative radiation Use of radio active colloid 43 pts with rectal cancer, Sensitivity of SN procedure 92%, Specitivity 90% 10% of patients with lower rectal cancer showed lateral SN’s
(Saha Ann Surg Oncol 2001, Bilchik eur J Cancer 2002)

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No pre-operative radiation in most cases Use of blue dye, in vivo and ex vivo SN detection by pathologist postoperatively 92 pts with rectal cancer , success rate 91% (failure associated with RT) No report on lateral nodes Sensitivity 92%, Specitivity 100%, Neg pred value 96% Upstaging 25%

Sentinel node – rectal cancer - results
• Germany (Bembenek et al, Surgery 2004)
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48 pts, 37 pts pre-operative radiotherapy SN detection with radio active colloid, ex vivo 46/48 pts SN identified Sensitivity 44%, false negative 56% SN only correctly predicted nodal status in pts without radiation In 4 pts SN outside the mesorectum, 1 node positive

The Netherlands (Braat et al, Br J Surg 2005)
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34 pts, all pre-operative radiotherapy SN detection with Patent blue dye, in vivo and ex vivo 26/34 pts SN identified Sensitivity 40%, false negative 60%, neg predictive value 73%

No SN after pre-operative radiation in rectal cancer

Sentinel node – Effect on staging in colon cancer

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Upstaging 18-30% with IHC at ≧ 3 levels
(Bilchik Ann Surg 2007, Kelder/Braat Int J Colorectal Dis 2007, Saha Am J surg 2006)

Aberrant lymphatic drainage 2-10% - (laparoscopy 30%)
(Bilchik Ann Surg 2007, Kelder/Braat Int J Colorectal Dis 2007, Saha Am J surg 2006)

Additional effect: blue dye assists the pathologist in identifying (small) lymph nodes with or without metastases

Sentinel node – staging and survival
Saha Am J Surg 2006 • • 500 pts with SN procedure in colorectal cancer (A), 368 pt control group (B) Success rate SN 98%, Sensitivity 90%, negative predictive value 93%, upstaging by IHC 26 % (54/207) Number of nodes: group A 15 vs group B 12 Nodal metastases: 50% group A pt vs 35% group B Recurrence rate after 2 yr follow up: 7% group A vs 25% group B • N0: 3% vs 18% • N+: 11% vs 37%

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Sentinel node – staging and survival
Bilchik et al Ann Surg 2007 – prospective multicenter trial

2 yr follow up of 92 pts with stage II colon cancer and SN procedure: 30% upstaging IHC + PCR 12 recurrences (all 12 with micrometastases) No recurrences in patients with negative SN (p=0.002)

Sentinel node in colon cancer- conclusions
• The SN procedure is feasible in colon cancer when:
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Patient selection is appropriate (stage I/II) The surgeon is well trained

The sentinel node procedure leads to upstaging (18-30%) through:
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Detection of aberrant lymphatic drainage (2-10%) Blue staining of the lymph nodes which assists the pathologist in detecting more and smaller nodes and the right nodes Ultrastaging by IHC/PCR

Upstaging might lead to stadium migration: some of the patients with micrometastases in the current stage II group are actually stage III patients

Sentinel node in rectal cancer- conclusions
• The SN procedure is not feasible in rectal cancer after pre-operative radiotherapy Without pre-operative radiotherapy, the SN is able to show lateral lymphatic drainage when present Radio-active colloid might be more accurate in rectal cancer because of the need for postoperative SN detection when leaving the mesorectum intact for the pathologist

SN procedure in colorectal cancer – future directions?

Rectal cancer:
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No SN procedure after pre-operative radiotherapy Without radiotherapy, the SN might be able to select patients for lateral lymphadenectomy in lower rectal cancer

Colon cancer:
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Upstaging by detection of micrometastases seems important for survival Prospective randomized trial to evaluate the effect of the SN procedure on recurrence and survival in patients with stage I/II colon cancer