sentinel node in colon cancer f. crafa, a. noviello · sentinel node in colon cancer f. crafa, a....

Francesco

Crafa

Sentinel node in colon cancer

F. Crafa, A. Noviello

General and Emergency Surgery Unit

Chief: F. Crafa M.D.

San Giuseppe Moscati Hospital

Hospital of National Relevance and High Specialty

Avellino

Italy

Francesco

Crafa

10–25% of the patients with localized colon

cancer (AJCC stage I and II) will develop

disease.

Up to 30 % of patients with colorectal cancer

diagnosed as pN0 following surgery will die

within 5 years owing to regional recurrence or

distant metastases.

Understaging is considered to be around 10–

20% , underlining the need to search for methods

that can help to achieve a correct staging of the

patient.

Saha S, Dan AG, Viehl CT et al (2005) Sentinel lymph node

mapping in colon and rectal cancer: its impact on staging,

limitations, and pitfalls. In: Leong SPL, Kitagawa Y, Kitajima M

(eds) Selective sentinel lymphadenectomy for human solid cancer.

Springer, New York pp 105–122

Mulsow J, Winter DC, O’Keane JC, O’Connell PR (2003) Sentinel

lymph node mapping in colorectal cancer. Br J Surg 90:659–667

Francesco

Crafa

Additional H&E histopathologic analysis of

serial sections allows for the identification of

micrometastatic disease in up to 20 % of

lymph nodes determined to be negative by

standard H&E methods.

Dionigi G, Castano P, Rovera F, et al. The

application of sentinel lymph node mapping in

colon cancer. Surg Oncol. 2007;16 Suppl

1:S129–32.

Francesco

Crafa

Therefore, what would be most useful and relevant is a

more careful evaluation of a selected group of

lymph nodes that have the highest probability of

containing metastatic cells, i.e., the sentinel lymph

nodes (SLNs).

Bilchik AJ, DiNome M, Saha S, et al. Prospective multicenter trial of staging adequacy in colon cancer: preliminary

results. Arch Surg. 2006;141:527–33.

Lim SJ, Feig BW, Wang H, et al. Sentinel lymph node evaluation does not improve staging accuracy in colon cancer.

Ann Surg Oncol. 2008;15:46–51.

Des Guetz G, Uzzan B, Nicolas P, et al. Is sentinel lymph node mapping in colorectal cancer a future prognostic

factor? A meta-analysis. World J Surg. 2007;31:1304–12.

Wood TF, Nora DT, Morton DL, et al. One hundred consecutive cases of sentinel lymph node mapping in early

colorectal carcinoma: detection of missed micrometastases. J Gastrointest Surg. 2002;6:322–9.

Broderick-Villa G, Ko A, O’Connell TX, et al. Does tumor burden limit the accuracy of lymphatic mapping and sentinel

lymph node biopsy in colorectal cancer? Cancer J. 2002;8:445–50.

Saha S, Seghal R, Patel M, et al. A multicenter trial of sentinel lymph node mapping in colorectal cancer: prognostic

implications for nodal staging and recurrence. Am J Surg. 2006;191:305–10.

Francesco

Crafa

In this regard, SLN mapping may allow

identification of a smaller number of

lymph nodes representing the tumor

status of the entire nodal basin. An

exhaustive analysis of SLNs in order to

achieve a more accurate staging of

patients can influence the decision for

adjuvant treatment.

Thorn M (2000) Lymphatic mapping and sentinel

node biopsy: is method applicable to patients with

colorectal and gastric cancer? Eur J Surg

166:755–758

Francesco

Crafa

A novel technique for pathological examination,

one step nucleic acid amplification (OSNA),

uses the reverse transcription loop-mediated

isothermal amplification (RTLAMP) method to

amplify cytokeratin 19 (CK19) mRNA. In contrast

to the current routine histopathological

examination, it is able to examine whole lymph

nodes (LNs) and detect metastases in a

sufficiently short time.

Tsujimoto M, Nakabayashi K, Yoshidome K, Kaneko T, Iwase T, Akiyama F,

et al. One-step nucleic acid amplification for intraoperative detection of

lymph node metastasis in breast cancer patients. Clin Cancer Res.

2007;13(16):4807–16.

Francesco

Crafa

CK19 mRNA copy numbers were calculated using a standard

curve that was established beforehand with three calibrators containing

different CK19 mRNA copy numbers. Standard positive and negative

control samples were used for quality assurance in every assay run. On

the basis of previous investigations, OSNA results with CK19 mRNA

copy numbers C 5000 copies/lL were designated as (++), and

OSNA results with CK19 mRNA copy numbers between 250 and

4999 copies/lL were designated as (+). OSNA results with fewer

than 250 copies/lL were considered negative results.

Tsujimoto M, Nakabayashi K, Yoshidome K, Kaneko T, Iwase T, Akiyama F, et al. One-step nucleic acid amplification for

intraoperative detection of lymph node metastasis in breast cancer patients. Clin Cancer Res. 2007;13(16):4807–16.

Notomi T, Okayama H, Masubuchi H, Yonekawa T, Watanabe K, Amino N, et al. Loop-mediated isothermal amplification

of DNA. Nucleic Acids Res. 2000;28(12):E63.

Mori Y, Nagamine K, Tomita N, Notomi T. Detection of loop mediated isothermal amplification reaction by turbidity

derived from magnesium pyrophosphate formation. Biochem Biophys Res Commun. 2001;289(1):150–4.

Francesco

Crafa

OSNA has already been introduced into clinical

settings for breast cancer patients worldwide. The

Japanese Breast Cancer guideline has

recommended OSNA as an alternative to

standard hematoxylin/eosin (H&E) staining for

intraoperative LN examination. OSNA was also

recommended by National Institute for Health

and Clinical Excellence (NICE) in the United

Kingdom, and has been published in the guideline

of the Spanish Society of Senology and

Mammary Pathology.

Visser M, Jiwa M, Horstman A, Brink, AA, Pol RP, van Diest P, et al. Intra-operative rapid diagnostic method based on CK19 mRNA expression for the

detection of lymph node metastases in breast cancer. Int J Cancer. 2008;122(11):2562–7.

Tamaki Y, Akiyama F, Iwase T, Kaneko T, Tsuda H, Sato K, et al. Molecular detection of lymph node metastases in breast cancer patients: results of a

multicenter trial using the one-step nucleic acid amplification assay. Clin Cancer Res. 2009;15(8):2879–84.

Bernet L, Cano R, Martinez M, Duenãs B, Matias-Guiu X, Morell L et al. Diagnosis of the sentinel lymph node in breast cancer: a reproducible

molecular method: a multicentric Spanish study. Histopathology. 2011;58(6):863–9.

Le Fre`re-Belda MA, Bats AS, Gillaizeau F, Poulet B, Clough KB, Nos C, et al. Diagnostic performance of one-step nucleic acid amplification for

intraoperative sentinel node metastasis detection in breast cancer patients. Int J Cancer. 2012;130(10):2377–86.

National Institute for Health and Care Excellence. NICE diagnostics guidance 8. Intraoperative tests (RD-100i OSNA system and Metasin test) for

detecting sentinel lymph node metastases in breast cancer. 2013.

Berneta L, Pin˜erob A, Vidal-Sicartc S, et al. Consensus on sentinel lymph node biopsy in breast cancer. Review of the Spanish Society of Senology

and Breast Pathology 2013. Revista de Senologıá y Patologıá Mamaria. Volume 27, Issue 1, January– March 2014, pp 43–53.

Francesco

Crafa

There are therefore two methods for

SLN mapping:

Staining method

Radioguided method

Francesco

Crafa

SLN mapping can be

performed

in vivo and ex vivo

Francesco

Crafa

Regarding the tracer used to detect the SLNs, three tracers

have been used: dye, RI, and ICG. Each tracer has its

respective disadvantages. The disadvantages of the dye

method are a low recognition rate and a short leveling time.

The high cost and the exposure problem of radioactivity are

disadvantages of RI tracers. The use of the ICG

fluorescence method has officially been approved in

Japan in LNs of breast cancer and malignant

melanoma, and it thus appears that ICG can be an

acceptable tracer for the detection of LNs in gastric and

colon cancer.

Staining Method

Francesco

Crafa

EXPERIENCE

Francesco

Crafa

Francesco

Crafa

Isolated LNs will be

analyzed with the OSNA

and traditional methods

according to the

procedure described by

Yamamoto (Ann. Surg.

Oncol. 2011)

Francesco

Crafa

Pat. Age Disease Intervention Stage LNs Copy Nodes LNs

weight

R.A.

Male

61 Adeno k

Left colon

(Polypectomy

pT1 G2 Haggit

level 4)

Open left

colectomy

(11/10/16)

pT1pN0pM0G2

Stage I

3 Neg.

(IMA)

(JSCCR

Level 3

253)

< 250 4 Nodes

retrieved

0,05

0,05

0,06

C.S.

Male

76 Adenok

Right colon

Polypectomy

(pT1, G2

Haggit level 4)

Open right

colectomy

(08/11/2016)

pT1pN0pM0G2

Stage I

2 Neg

(Interm.,

Ileocolic)

(JSCCR

Level 2

202)

<250 32 Nodes

retrieved

0,25

0,08

C.G.

Female

47 Adenok

left colon

(Polypectomy

pT1, G2)

Laparoscopic

Left Colectomy

(24/11/2016)

pT1pN0pM0G2

Stage I

1 Neg

(IMA)

(JSCCR

Level 3

253)

<250 19 Nodes

retrieved

0,10

B.M.

Male

80 Adenok

High rectum

Polypectomy

pT1, G2

Kikuchi sm3)

Laparoscopic

pTME

(24/11/2016)

pT1pN0pM0G2

Stage I

1 Neg

(IMA)

(JSCCR

Level 3

253)

< 250 8 Nodes

harvested

0,08

< 250 copy = neg.

> 250 copy = pos.

Experience (20 Patients)

(STAGE I / II)

Francesco

Crafa


weight

S.F.

Male

68 Adeno k

Left Colon

Lap. Left

Colect.

(17/05/16)

pT2 pN0 pM0 G2

Stage I

1 Neg.

(IMA)

(JSCCR

Level 3

253)

< 250 15 Nodes

retrieved

0,05

C.C.

Female

72 Adenok

Right colon

Open

Right

Colectomy

(19/12/2016)

pT3pNopMoG2

Stage II A

1 Neg

(Ileocolic)

(JSCCR

Level 2

202)

<250 20 Nodes

harvested

0,08

G.P.

Male

71 Adeno k

Left Colon

Lap Left

Colect.

(17/05/16)

pT3 pN0 pM0 G2

Stage II A

1 Neg.

(IMA)

(JSCCR

Level 3

253)

< 250 18 Nodes

retrieved

0,06

M.V.

Male

83 Adeno k

Rect Sigmoid

Open pTME

(07/07/16)

pT3 pN0 pM0 G2

Stage II A

1 Neg.

(IMA)

(JSCCR

Level 3

253)

< 250 6 Nodes

retrieved

0,07

< 250 copy = neg.

> 250 copy = pos.


(STAGE I / II)

Francesco

Crafa


weight

DP.D.

Female

82 Adeno k

Left Colon

Open Left

Colect.

(21/09/16)

pT3 pN0 pM0 G2

Stage II A

1 Neg.

(IMA)

(JSCCR

Level 3

253)

< 250 6 Nodes

retrieved

0,05

A.R.

Male

84 Adenok

Left colon

Open

Left Colectomy

(01/12/16)

pT4pN0pM0G2

Stage II B

3 Neg

(IMA)

(JSCCR

Level 3

253)

< 250 23 Nodes

harvested

0,43

0,17

0,14

P.C.D.

Male

61 AdenoK

Rectosimoid

junction

Open

pTME

(18/01/17)

pT3pN0pM0G2

Stage II A

1 Neg.

(SHA)

(JSCCR

Level 2

253)

< 250 31 Nodes

harvested

0,43

< 250 copy = neg.

> 250 copy = pos.


(STAGE I / II)

Francesco

Crafa


weight

I.F.

Fem.

70 Adeno k

High Rectum

Open

pTME.

(05/10/16)

pT1pN1cpM0 G2

Stage III A

2 Neg.

(IMA)

(JSCCR

Level 3

253)

< 250 1 Tumor deposit

located subseros.

5 Nodes retrieved

0,11

0,06

C.C.

Male

81 Adeno k

Left Colon

Open Left

Colect.

(17/03/16)

pT3 pN1c pM0 G3

Stage III B

1 Pos

(IMA)

(JSCCR

Level 3

253)

280 Subserosal

Infiltration of one

node

18 Nodes retrievied

0,18

C.G.

Male

86 Adeno k

Right Colon

Open Right

Colect.

(05/10/16)

pT3pN1pM0 G2

Stage III B

1 Pos.

(Peric.)

(JSCCR

Level 1

201)

1600 1 Met.

37 Nodes retrieved

0,22

F.L.

Fem.

43 Adenok

Splenic

Flexure

Open

Splenic

Flexure

Resection

(23/12/2016)

pT3pN1apM0G3

Stage III B

1 Pos

(Paracolic)

(JSCCR

Level 1

221)

62000 1 Met

8 Nodes

harvested

0,50

0,17

< 250 copy = neg.

> 250 copy = pos.


(STAGE III / IV)

Francesco

Crafa


weight

P.A.

Male

70 Adeno k

Stenosis

High rectum

Open TME

(30/06/16)

pT4 pN2b pM0 G3

Stage III C

1 Pos.

(SHA)

(JSCCR

Level 1

251)

250000 14 Met.

28 Nodes

retrieved

0,08

G.E.

Female

51 Adenok

High rectum

Open pTME

(10/11/2016)

pT3pN2bpV1pMOG3

Stage III C

2 Pos

(paracol.)

(JSCCR

Level 1

251

241)

380000

2500

9 Met

17 Nodes

retrieved

0,51

0,17

P.A.

Male

59 Adenok

Right colon

Open

Right

Colectomy

(22/12/2016)

pT4apN2bpM0G2

Stage III C

1 Pos

(Ileocolic)

(JSCCR

Level 2

202)

27000 14 Met

24 Nodes

harvested

0,20

< 250 copy = neg.

> 250 copy = pos.


(STAGE III / IV)

Francesco

Crafa


weight

S.G.

Male

70 Adeno k

Right Colon

Liver Met

Open Right

Colect.

(13/09/16)

pT3 pN1 pM1(hep)

G2

Stage IV A

1 Pos.

(ICA)

(JSCCR

Level 2

202)

7800 2 Met.

26 Nodes

retrieved

0,55

K.O.

Female

45 Adenok

Right colon

Open right

colectomy

(14/10/16)

pT4pN1pM1

(omentum, ovary) G3

Stage IV A

1 Pos

(Interm.,

Ileocolic)

(JSCCR

Level 2

202)

380000 1 Met

51 Nodes

retrieved

1,80

< 250 copy = neg.

> 250 copy = pos.


(STAGE III / IV)

Francesco

Crafa

DISCUSSION

Int J Colorectal Dis (2015) 30:303–314Francesco

Crafa

J Am Coll Surg 2014;218:969-977

Figure 2. Scope of lymph node

dissection in Japan.

• Left-sided and rectosigmoid

colon. The double, parallel

blue lines indicate transection

points for the vessels.

Analysis of data from the

Japanese Cancer Registry

demonstrated that LN metastasis

around the origin of the feeding

artery occurred in 0.7% and 2.7%

to 7.6% of patients with pT2 and

pT3 or pT4 tumors, respectively.

For cT3 and cT4 diseases, D3

dissection is recommended.

For cT1 and cT2 diseases, D3

dissection is indicated in the

case of clinically apparent LN

metastasis.Francesco

Crafa

Francesco

Crafa

Lymphatic drainage and regional lymph nodes associated with the colon

Several studies show that in more than 80 % of cases, the first

metastatic lymph node in colorectal cancer is a paracolic lymph node

located 5 cm or less from the tumor.

Bembenek A.

Current clinical status of

sentinel lymph nodes in

colon and proximal rectal

cancer.

Colorectal Dis. 2011;13 Suppl

7:63–6.

Francesco

Crafa


Beside this classic lymphatic drainage, aberrant

drainage within the regional lymph nodes can exist.

Such drainage leads directly to main lymph node

stations near the superior and inferior mesenteric

vessels or to colic and paracolic lymph nodes

located at a significant distance from the tumor.

The prevalence of aberrant lymphatic drainage has

generally been reported to be up to 20 % .

Bilchik AJ, Saha S, Wiese D, et al. Molecular staging of early colon cancer on the basis of sentinel node

analysis: a multicenter phase II trial. J Clin Oncol. 2001;19:1128–36.

Wood TF, Tsioulias GJ, Morton DL, et al. Focused examination of sentinel lymph nodes upstages early

colorectal carcinoma. Am Surg. 2000;66:998–1003.

Saha S, Johnston G, Korant A, et al. Aberrant drainage of sentinel lymph nodes in colon cancer and its

impact on staging and extent of operation. Am J Surg. 2013;205:302–5.

Francesco

Crafa


Drainage of this nature influences the scope of lymphadenectomy

since “aberrant” lymph nodes are potential locations for “skip

metastases”. In some cases, the first lymph nodes to become

dyed are those on the opposite side of the colon. Instances of

lymphatic drainage from the transverse colon through the

greater omentum to the splenic hilar lymph nodes have also

been published. Moreover, tumors located in the hepatic flexure

can, in about 5 % of cases, metastasize to lymph nodes located

around the head of pancreas and in about 4 % of cases to

omental lymph nodes .

Iddings D, Bilchik A. The biologic significance of micrometastatic disease and sentinel lymph node

technology on colorectal cancer. J Surg Oncol. 2007;96:671–7.

Wood TF, Nora DT, Morton DL, et al. One hundred consecutive cases of sentinel lymph node mapping in

early colorectal carcinoma: detection of missed micrometastases. J Gastrointest Surg. 2002;6:322–9.

Saha S, Monson KM, Bilchik A, et al. Comparative analysis of nodal upstaging between colon and rectal

cancers by sentinel lymph node mapping: a prospective trial. Dis Colon Rectum. 2004;47:1767–72.

Tsioulias GJ, Wood TF, Spirt M, Morton DL, Bilchik AJ. A novel lymphatic mapping technique to improve

localization and staging of early colon cancer during laparoscopic colectomy. Am Surg. 2002;68:561–5.

Hohenberger W, Weber K, Matzel K, et al. Standardized surgery for colonic cancer: complete mesocolic

excision and central ligation-technical notes and outcome. Colorectal Dis. 2009;11: 354–64.

Robert S. Grinnell. Lymphatic Block with Atypical and Retrograde LymphaticMetastasis and Spread in Carcinoma of the Colon and Rectum. Ann Surg. 1966Feb;163(2):272-80

Francesco

Crafa

One of the largest studies analyzed 192 patients with colon cancer.

In 42 (22 %) patients, aberrant lymphatic drainage was observed

which changed the scope of the resection. In 19 patients with

extended scope of resection, metastases were found in lymph

nodes located beyond the standard resection margin, and in two

of these patients, these lymph nodes were the only sites of

metastases. Furthermore, metastases to lymph nodes were

detected in 62 % of patients in whom the scope of resection was

extended after lymphatic mapping, compared with only 43 % of

those who underwent standard resection. In the extended resection

group, an average of 17.6 lymph nodes was examined, while in the

standard resection group, the average was 15.8. Analysis of the data

indicates that aberrant lymphatic drainage influences disease

management, assessment of the disease stage, and, to a limited

extent, survival.

Saha S, Johnston G, Korant A, et al. Aberrant drainage of

sentinel lymph nodes in colon cancer and its impact on staging

and extent of operation. Am J Surg. 2013;205:302–5.

Francesco

Crafa

Relationship of tumor (T) stage to nodal status

Francesco

Crafa

In a study in 2014, 55 patients with colon cancer after

SLN biopsy were compared with a control group of 110

patients adjusted for tumor-related factors and operated

on without SLN biopsy. The average number of

examined lymph nodes in the clinical and control

group differed significantly, being nine and seven,

respectively ( p = 0.03).

Braat AE, Pol RA, Oosterhuis JW, et al. Excellent prognosis of node negative

patients after sentinel node procedure in colon carcinoma: a 5-year follow up study.

Eur J Surg Oncol. 2014;40:747–55.

Francesco

Crafa

Immunochemistry resulted in upstaging owing to the

detection of metastases in 3 of 38 SLNs initially

considered true negative. The 5-year survival rates

differed significantly in the two groups: 83 % in the SLN

biopsy group vs. 69 % in the control group with no

SLN biopsy ( p = 0.03). Furthermore, within the SLN

group, the 5-year survival rate was higher in SLN

negative patients (91 % vs. 76 %; p = 0.04). The authors

emphasized the excellent prognosis in SLN-negative

patients when using H&E stain and immunochemistry

together with automated microscopy.

Braat AE, Pol RA, Oosterhuis JW, et al. Excellent prognosis of node negative

patients after sentinel node procedure in colon carcinoma: a 5-year followup study.

Eur J Surg Oncol. 2014;40:747–55.

Francesco Crafa

Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD. Prognostic factors in colorectal carcinomas arising inadenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology. 1985Aug;89(2):328-36

Levels of invasion in a pedunculated adenoma (left) and a sessile adenoma (right). The stippled areas represent zones ofcarcinoma. Note that any invasion below the muscularis mucosae in a sessile lesion represents level 4 invasion, i.e.,invasion into the submucosa of the bowel wall. In contrast, invasive carcinoma in a pedunculated adenoma (left) musttraverse a considerable distance before it reaches the submucosa of the underlying bowel wall. The dotted line in thehead of the pedunculated adenoma represents the zone of level 1 invasion. Although more pedunculated adenomashave a tubular pattern and most sessile adenomas are villous, exceptions to this generalization occur.

Haggitt levelspedunculated lesions

Francesco Crafa

Kikuchi R, Takano M, Takagi K, Fujimoto N, Nozaki R, Fujiyoshi T, Uchida Y. Management of early invasivecolorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum. 1995 Dec;38(12):1286-95.

Figure 1, Classification of level of invasion of early invasive cancer (from classification at CancerInstitute Hospital, Tokyo).

Sm1: slight submucosal invasion fromthe muscularis mucosa.

Sm2: intermediate between sm1 and sm3.

Sm3: carcinoma invasion near the inner surfaceof the muscularis propria

Kikuchi levelsT1 cancers

Francesco Crafa

Wai Lun Law, Conor P. Delaney. Single Incision Laparoscopic and Transanal Colorectal Surgery. Springer 2014

Francesco Crafa

Eur J Cancer. 2013 Mar;49(5):1104-8

Risk stratification indexshowing the increase in riskfor lymph node metastases(%) in T1 and T2 tumoursrespectively when addingrisk factors one at a time.The variables chosen forinclusion into the risk indexare the variables withstatistical significance in themultivariate analysis:

a. poor differentiation;b. vascolar invasion.

Francesco Crafa

Macias-Garcia F, Celeiro-Muñoz C, Lesquereux-Martinez L, Gude-Sampedro F, Uribarri-Gonzalez L, AbdulkaderI, Alvarez-Castro A, Dominguez-Muñoz JE. A clinical model for predicting lymph node metastasis insubmucosal invasive (T1) colorectal cancer. Int J Colorectal Dis. 2015 Jun;30(6):761-8

Fig. 2 Estimated risk of lymph node metastasis (LNM) according to the predictionmodel. It has been established a score range from 0 to 100 points, depending onthe score obtained by each of the variables included in the prediction model.Dotted line located at 35 points (i.e., 10 % risk LNM) indicates our cutoff point toindicate an additional surgery after a T1-CRC endoscopic resection.

The probability of LNM is always less than 10 % if the patient has onlyone criterion, but it is higher when at least two of the criteria arepresent. Therefore, the benefit-risk balance is in favor of surgery whenat least two histopathological criteria are present.

Francesco

Crafa

Francesco

Crafa

Published evidence

Three prospective observational studies were

selected for inclusion (n=2,232 lymph node [LN]

specimens from 253 people) and reported that

the diagnostic performance of OSNA was

better than standard histopathology.

Francesco

Crafa

Table 2 summarises the clinical evidence as well as its

strengths and limitations.

Francesco

Crafa

Table 2 summarises the clinical evidence as

well as its strengths and limitations.

Francesco

Crafa

Table 2 summarises the clinical evidence as well

as its strengths and limitations.

Francesco

Crafa

Strengths and limitations of the

evidence

Although all the studies were prospective in design,

none were randomised controlled trials which would

have helped to systematically control for biases. All 3

studies were observational rather than randomised

controlled studies.

Two studies investigated OSNA in LNs, and 1 study

assessed OSNA in sentinel LNs. LNs have a differing

potential to sentinel LNs to harbour metastases, so

the study results may not be directly comparable.

Francesco

Crafa

Yamamoto performed a clinical study based on

385 LNs, and concluded that OSNA is

comparable to a 2 mm interval

histopathological examination in its ability to

detect LN metastases.

Yamamoto H, Sekimoto M, Oya M, Yamamoto N, Konishi F, Sasaki J, et al.

OSNA-based novel molecular testing for lymph node metastases in colorectal

cancer patients: results from a multicenter clinical performance study in Japan.

Ann Surg Oncol. 2011;18(7):1891–8.

Francesco

Crafa

Francesco

Crafa

Examination of 1925 LNs at a variety of TNM

stages revealed 95.7 % concordance, 86.2 %

sensitivity, and 96.5 % specificity when every LN

was halved and examined using both H&E staining

and the OSNA assay. Only 20 of 1925 LNs (1.0%)

were H&E-positive and OSNA-negative. This

discrepancy could be attributed to allocation bias

(uneven location of metastatic tumor cells), as

previously described.

Yamamoto H, Sekimoto M, Oya M, Yamamoto N, Konishi F, Sasaki J, et

al. OSNA-based novel molecular testing for lymph node metastases in

colorectal cancer patients: results from a multicenter clinical performance

study in Japan. Ann Surg Oncol. 2011;18(7):1891–8.

Francesco

Crafa

In contrast, 63 of 1925 LNs were H&E-

negative, yet OSNA-positive (3.3 %).

Overall, the results led to the upstaging

of TNM stage in 11.3 % of patients with

stage I and stage II disease and 7.1 %

for stage III patients.

Francesco

Crafa

Among 204 CRC patients, 124 cases were

node-negative at stage I and stage II. OSNA

positive cases were observed in 2.0 % of

stage I CRC and 17.6 % (13 of 74 cases) of

stage II CRC; these cases had more advanced

features of CRC, such as deeper invasion to

the colonic wall and severe invasion to

lymphatic invasion compared with OSNA-

negative cases.

Francesco

Crafa

CONCLUSION

Francesco

Crafa

IMPROVE STAGING BY A FOCUSED ULTRASTAGING

EXAMINATION OF THE SNs

OSNA IS SIMILAR TO A 2 MM INTERVAL H.E. WITH

H&E SECTIONS.

OSNA STAGING USING THE WHOLE LNs

UPSTAGE COLONIC CANCER

ADDITIONAL RISK FACTOR FOR D.R. IN STAGE II

CRC

ADJUVANT TREATMENT

ORGAN SPARING SURGERY

TAILORED LYMPHADENECTOMY

ABERRANT AND SKIP METASTASES

QUALITY OF THE LIMPHADENECTOMY

NOVEL MOLECULAR STAGING

Francesco

Crafa

Therefore, false-negative cases would be exceptional if whole

LNs were subject to OSNA. UICC classification distinguishes

TNM stages between < 3 LN metastases and > 4 LN metastases.

Yamamoto found that the sum of CK19 mRNA increased as the

number of histologically positive LNs increased. Indeed, the

median value of CK19 mRNA was significantly smaller in

patients with < 3 regional LN metastases than in those with >

4 regional LN metastases.

These findings indicate that sum of CK19 mRNA assessed by

OSNA displays a trend compatible to the current pathological

diagnosis system. These findings suggest the future possibility

of novel molecular staging using OSNA, based on metastasis

volume (amount of CK19 mRNA) rather than number of LN

metastases.

Francesco

Crafa

ICG AND OSNA are the

route to tailor-made

surgery

Francesco Crafa

Francesco

Crafa

Sentinel node in gastric cancer

F. Crafa, A. Noviello

General and Emergency Surgery Unit

Chief: F. Crafa M.D.

San Giuseppe Moscati Hospital

Hospital of National Relevance and High Specialty

Avellino

Italy

Francesco

Crafa

SN is defined as the first LN to receive

cancer cell drainage from the primary

tumor, and the LN to which cancer cells

metastasize at the beginning. The idea that

the tumor status of SN reflects

“efficiently” the status of the other LNs

represents the main concept of this

technique.

Sentinel node (SN)

Francesco

Crafa

Minimally invasive surgery such as limited

LN dissection and reduced extent of

resection based on SN mapping is termed

SN navigation surgery (SNNS). This

surgery may prevent the post-operative

complications and serve as a useful tool

for avoiding an over invasive surgery.

Sentinel node navigation surgery

(SNNS)

Francesco Crafa

Chang-Ming Huang, Chao-Hui Zheng. Laparoscopic Gastrectomy for Gastric Cancer. Springer 2015

The lymphatic drainage of the stomach is customarily divided intofour areas according to the four feeding arteries of the gastric walls:

District I(right gastroepiploic artery (RGEA) group): This lymphaticnetwork mainly drains the greater curvature of the lower half ofthe gastric body and the pylorus.

District II

(left gastroepiploic and short gastric arteries group): Thislymphatic network mainly drains the greater curvature of the lefthalf of the gastric fundus and the greater curvature of the upperhalf of the gastric body.

District III(left gastric artery (LGA) group): This lymphatic network mainlydrains the right half of the fundus, left half of the lessercurvature, and cardia of the stomach.

District IV(right gastric artery (RGA) group): This area mainly drains thelesser curvature of the gastric pylorus.

Francesco Crafa

In addition to the general LNM pattern via the lymph vessels, someparticular LNM patterns may occur as follows:

Chang-Ming Huang, Chao-Hui Zheng. Laparoscopic Gastrectomy for Gastric Cancer. Springer 2015

Retrograde metastasis

The lymph vessels among different districts communicate with oneanother, and retrograde motion may exist even under normal conditions.Additionally, cancer emboli may obstruct the lymphatic vessels or LNs,increasing the risk of retrograde movement.

Skipmetastasis

Metastatic spread may skip regional draining LNs to form distant nodalmetastases via the collateral branches of the lymph vessels. Therefore, itis important for the surgeon to dissect the distal LNs during surgery.

Virchow ’ s metastasis

The supraclavicular LNs are located at the point at which the thoracicduct drains into the left jugular vein. Metastasis of these LNs is calledVirchow’s metastasis. Metastasis of Virchow’s node is considered to bestrongly indicative of the presence of extensive metastasis in theretroperitoneal tissue around the abdominal aorta.

Francesco

Crafa

In general, SN mapping and biopsy is

indicated in:

(I) patients with T1 or T2 tumors;

(II) primary lesions < than 4 cm in

diameter;

(III) clinical N0 gastric cancer.


(SNNS)

Takeuchi H, Kitagawa Y. New sentinel node mapping technologies for early gastric

cancer. Ann Surg Oncol 2013;20:522-32.

Kitagawa Y, Takeuchi H, Takagi Y, et al. Sentinel node mapping for gastric cancer: a

prospective multicenter trial in Japan. J Clin Oncol 2013;31:3704-10.

Francesco

Crafa

A recent study demonstrated that 91% of patients with

T1 tumors and 88% with T2 tumors had stained SLNs

as compared to only 68% of patients with T3 tumors.

SN mapping in T1 and T2 gastric cancers may be

useful in the decision-making process with regard to

the extent of lymphadenectomy.

As well as for other cancer types, SN mapping should

not be performed in cases with positive LN metastasis

identified by preoperative imaging diagnostic modalities

such as ultrasonography and CT


(SNNS)

Takeuchi H, Kitagawa Y. New sentinel node mapping technologies for early gastric

cancer. Ann Surg Oncol 2013;20:522-32.

Kitagawa Y, Takeuchi H, Takagi Y, et al. Sentinel node mapping for gastric cancer: a

prospective multicenter trial in Japan. J Clin Oncol 2013;31:3704-10.

Francesco

Crafa

Moreover, a different and innovative type of

fluorescence imaging system was recently developed

for SN navigation surgery. The photodynamic eye

(PDE) is able to visualize ICG fluorescence emitted by

a light-emitting diode. The PDE visualizes SNs and

lymphatic vessels more clearly than the usual ICG

method. However, it is necessary to make the

operating room pitch-darkness for detecting SLNs

while performing SN mapping.


(SNNS)

Kusano M, Tajima Y, Yamazaki K, et al. Sentinel node mapping guided by indocyanine

green fluorescence imaging: a new method for sentinel node navigation surgery in

gastrointestinal cancer. Dig Surg 2008;25:103-8.

Francesco

Crafa

Novel, sophisticated ICG fluorescence systems

such as the D-light P system do not need for

switching off the lights in order to detect SN.

What is more, with this novel system, SN

examination even in laparoscopic surgery can

be safely performed. Therefore, in the near

future, this method could become the standard

method to detect SN in GI malignancies.


(SNNS)

Francesco

Crafa

Francesco

Crafa

Patients with previously untreated

Ct1n0m0 gastric adenocarcinomas

less than 4 cm in gross diameter

were eligible for inclusion in this

study.

Francesco

Crafa

Francesco

Crafa

Notably, the diagnostic accuracy

of SN mapping for cT2 tumors is

currently suboptimal; therefore,

we believe that the clinical

application of SN mapping should

be limited to cT1 tumors.

Francesco

Crafa

Francesco

Crafa

In addition, after detecting the SN, the next step is the biopsy.

Intraoperative diagnosis using hematoxylin and eosin (H-E)

staining of a frozen section from the LN represents the gold

standard technique for SN biopsy. However, the reliability of frozen

section examination has been under evaluation. In this way, in a

Japanese multicenter trial, it was found that ~25% of patients

with SN metastases that were diagnosed using permanent

sections could not be identified using H-E staining of frozen

sections collected intraoperatively.


(SNNS)

Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010

(ver. 3). Gastric Cancer 2011;14:113-23.

Kitagawa Y, Takeuchi H, Takagi Y, et al.

Sentinel node mapping for gastric cancer: a prospective multicenter trial in Japan. J Clin

Oncol 2013;31:3704-10.

Francesco

Crafa

Multistep level sections, immunohistochemistry,

reverse transcription polymerase chain reaction

(RT-PCR), and the one-step nucleic acid

amplification assay (OSNA), have all been

developed to reduce the false-negative rates

and provide reliable diagnostic tools for

micrometastases in SN.


(SNNS)

Takeuchi H, Ueda M, Oyama T, et al. Molecular diagnosis and translymphatic chemotherapy targeting sentinel

lymph nodes of patients with early gastrointestinal cancers. Digestion 2010;82:187-91.

Kumagai K, Yamamoto N, Miyashiro I, et al. Multicenter study evaluating the clinical performance of the OSNA

assay for the molecular detection of lymph node metastases in gastric cancer patients. Gastric Cancer

2014;17:273-80.

Yanagita S, Natsugoe S, Uenosono Y, et al. Detection of micrometastases in sentinel node navigation surgery

for gastric cancer. Surg Oncol 2008;17:203-10.

Francesco

Crafa

Moreover, Kumagai et al. demonstrated that the

sensitivity and specificity of the OSNA assay was

higher than conventional examination. Recently, it

has been possible to reduce the detection time to ~30

min, and these innovative techniques have also raised

the sensitivity to detect SN metastases as part of the

intraoperative diagnostic algorithm.


(SNNS)

Takeuchi H, Ueda M, Oyama T, et al. Molecular diagnosis and translymphatic chemotherapy targeting sentinel

lymph nodes of patients with early gastrointestinal cancers. Digestion 2010;82:187-91.

Kumagai K, Yamamoto N, Miyashiro I, et al. Multicenter study evaluating the clinical performance of the OSNA

assay for the molecular detection of lymph node metastases in gastric cancer patients. Gastric Cancer

2014;17:273-80.

Yanagita S, Natsugoe S, Uenosono Y, et al. Detection of micrometastases in sentinel node navigation surgery

for gastric cancer. Surg Oncol 2008;17:203-10.

Francesco

Crafa

Francesco

Crafa

In this study, the OSNA assay was shown to provide a

diagnostic ability equivalent to that of the

postoperative 2-mm-interval histological

examination, as the concordance rate between the

two methods for 394 LNs from 61 patients was 0.942

(95 % CI, 0.914–0.963), in which the lower limit of the

95 % CI exceeded the predetermined target value of

0.83. In addition, this study also showed that the

specificity of the OSNA assay for detecting LN

metastases in 32 ‘‘node-negative patients’’ was 0.991

(95 % CI, 0.966–0.999).

Francesco

Crafa

There were 23 discordant results between the OSNA

assay and histological examination: 14 LNs were

histologically negative but positive in the OSNA

assay, and 9 LNs were histologically positive but

negative in the OSNA assay. As the LN blocks used

for the OSNA assay and histological examination were

obtained from different parts of the LN, discordant

results between the methods cannot be completely

avoided for reasons of tissue allocation bias: the

metastasis could be localized in the blocks used for the

OSNA assay or in the blocks for histology.

Francesco

Crafa


weight

P.V.

Male

68 Adeno k

Body

Total

gastrectomy + d

2 lymph.

(18/10/2016)

pT4apN0pM0 G3 Neg.

Great

curvature

5 nodes

Station 4d /

4sb

< 250 76 nodes

retrieved

0,15

D.N.P.

Male

82 Adeno k of the

gastric stump

Total

gastrectomy +

d2 lymph.

(26/10/2016)

pT3pN1pM0 G2 Neg.

Lesser

curvature

Left gastric

artery

1 node

Station 7

<250 1

metastasis

(station 3)

11 nodes

retrieved

0,08

P.A.

Male

64 Adeno k

Body

Total

gastrectomy +

d2 plus lymph.

(26/10/2016)

pT4pN1pM0 G2/G3 Neg.

Great

curvature

1 node

Station 4d

<250 1

metastasis

(station 3)

35 nodes

retrieved

0,10

S.F.

Fem.

78 Adeno k

Body

Total

gastrectomy +

d2 lymph

(01/02/2017)

pT2pN2pM0 G2 Pos (1)

Lesser

curvature

LGA basin

4 nodes

4700 3

metastasis

25 nodes

retrieved

0,76

0,10

0,3

1,5

< 250 copy = neg.

> 250 copy = pos.


Francesco

Crafa

Improve staging by a focused ultrastaging

examination of the SLNs:

OSNA is similar to a 2 mm interval HE and

is using the whole LN.

Concordance rate between the two

methods for 394 LNs from 61 patients was

0.942

Specificity of the OSNA assay for

detecting LN metastases in 32 ‘‘node-

negative patients’’ was 0.991

Conclusions

Francesco

Crafa

We have to take into account histological

type of primary tumour, CK19 expression

of primary tumour, tissue allocation bias.

Usefull for organ sparing surgery, tailored

and successful lymphadenectomy and

aberrant and skip metastases.(Sentinel

nodes navigation surgery)

Conclusions

sentinel node in colon cancer f. crafa, a. noviello · sentinel node in colon cancer f. crafa, a....

Documents