The Sentinel Node (SN) in Colorectal Cancer

7/31/2019 The Sentinel Node (SN) in Colorectal Cancer

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The sentinel node (SN) in colorectal cancerThe sentinel node (SN) in colorectal cancer

Prof R.A.E.M. Tollenaar

Dr W. Kelder


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The SN in colorectal cancer- overview of presentationThe 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


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TNM stage and prognosisTNM stage and prognosis

20 % of stage II patients will develop recurrence in spite of an apparentlyevident surgical cure

Causes? 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, highrisk stage II patients


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Quality of the surgical resection vs prognosisQuality 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)


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Quality of the pathological examination vs prognosisQuality 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)


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Pathological examination standard techniquePathological examination standard technique

Fixation in 10% buffered formalin (1 night)

Lymph node retrieval by palpation and visualization

One section if node1.0 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


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Methods to improve lymph node stagingMethods 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)

Ultrastaging 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)

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


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Lymph node sampling - micrometastasesLymph node sampling - micrometastases

Iddings et al Ann Surg Oncol 2006 meta-analysis

Retrospective molecular detection of metastases by RT-PCR shows anadverse effect on survival in stage II patients

IHC detected micrometastases do not have a significant effect onsurvival (there is a survival difference, no significance due toheterogeneity in studies)


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Sentinel lymph node (SN)Sentinel lymph node (SN)

Sentinel node:

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

*Morton et al, Arch surg 2002


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SN procedure - historySN procedure - history 1923 Braithwaite lymphatic flow from ileocecal valve with indigocarmine

1950 Weinberg - lymphatic mapping with pontine sky blue to identify thethoracic duct and lymph nodes in gastric and pulmonary cancer

1960 Gould SN in parotid carcinoma

1977 Cabaas 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 implicationsSentinel node clinical implications

Melanoma and breast cancer 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 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


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Sentinel node colorectal lymphatic drainageSentinel node colorectal lymphatic drainage

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


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Sentinel node colorectal lymphatic drainageSentinel node colorectal lymphatic drainage

Distribution of sentinel nodes in colorectal cancer (Kitagawa Dis Col Rectum 2002)


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Sentinel node rectal lymphatic drainageSentinel node rectal lymphatic drainage

Difference between upper and lower rectum (middle Houstons valve)

Upper rectum: predominantly upward drainage associated with the inferiormesenteric artery similar to colon TME

Lower rectum: lateral lymphatic channels along the lateral ligament (middlerectal artery) towards the lateral pelvic and internal iliac nodes

Japan: lateral pelvic lymphadenectomy in patients with T3/4 cancers belowthe peritoneal reflection


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Rectal cancer lateral node involvementRectal cancer lateral node involvement

Risk factors: involved mesorectal nodes, female sex, advanced T-stage,lymphovascular invasion

Yano Br J Surg 2008


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Rectum lateral lymphadenectomyRectum lateral lymphadenectomy


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Sentinel node in colorectal cancer techniqueSentinel node in colorectal cancer technique

Technique in vivo or ex vivo

Injection of 1-2 ml blue dye / radioactive colloid subserosally in 4 quadrants aroundthe 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 techniqueSentinel node technique


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Sentinel node techniqueSentinel node technique


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Sentinel node technique / resultsSentinel node technique / results

SN colon cancer in experienced hands* Success rates 92-94%

Sensitivity 89-94 % Negative predictive value 93-94%

Meta-analysis 2007 (world J surg 2007, des guetz et al) 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 DisCol Rectum 2002, Saha Ann Surg Oncol 2001 )


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Sentinel node rectal cancerSentinel node rectal cancer

Very interesting regarding lateral lymphatic drainage, however*:

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


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Sentinel node rectal cancer - resultsSentinel node rectal cancer - results

Japan (Kitagawa Dis Col Rectum 2002) 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 SNs

USA (Saha Ann Surg Oncol 2001, Bilchik eur J Cancer 2002) 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%


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Sentinel node rectal cancer - resultsSentinel node rectal cancer - results

Germany (Bembenek et al, Surgery 2004) 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) 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


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Sentinel node Effect on staging in colon cancerSentinel node Effect on staging in colon cancer

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) lymphnodes with or without metastases


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Sentinel node staging and survivalSentinel 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 IHC26 % (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 survivalSentinel 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)


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Sentinel node in colon cancer- conclusionsSentinel node in colon cancer- conclusions

The SN procedure is feasible in colon cancer when: Patient selection is appropriate (stage I/II)

The surgeon is well trained

The sentinel node procedure leads to upstaging (18-30%) through: Detection of aberrant lymphatic drainage (2-10%)

Blue staining of the lymph nodes which assists the pathologist in detectingmore and smaller nodes and the right nodes

Ultrastaging by IHC/PCR

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


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Sentinel node in rectal cancer- conclusionsSentinel node in rectal cancer- conclusions

The SN procedure is not feasible in rectal cancer after pre-operativeradiotherapy

Without pre-operative radiotherapy, the SN is able to show lateral lymphaticdrainage when present

Radio-active colloid might be more accurate in rectal cancer because of theneed for postoperative SN detection when leaving the mesorectum intactfor the pathologist


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The Sentinel Node (SN) in Colorectal Cancer