Lymph nodes in gastric cancer

Journal of Surgical Oncology 2008;98:476–481

REVIEW

Lymph Nodes in Gastric Cancer

M. MAHIR OZMEN, MD, MS, FACS, FRCS,1* FUSUN OZMEN, MD, MSci, PhD,2 AND BARIS ZULFIKAROGLU, MD1

1Department of Surgery, Ankara Numune Teaching and Research Hospital, Ankara, Turkey2Department of Basic Oncology, Institute of Oncology, Hacettepe University, Ankara, Turkey

Surgery is the only curative therapy for gastric cancer and controversy still exist on the extend of surgery. As the lymphatic distribution of stomach

is very complex, the determination of the actual lymph node involvement is important for making the decision in order to avoid complications.

Sentinel node navigation surgery has recently been introduced in gastrointestinal tract cancer. Present article reviews the detection techniques of

lymph nodes and significance of lymphadenectomies in gastric cancer.

J. Surg. Oncol. 2008;98:476–481. � 2008 Wiley-Liss, Inc.

KEY WORDS: gastric cancer; lymph nodes; surgery

INTRODUCTION

Gastric cancer is the second most common cancer death worldwide

[1]. Surgery is the only curative therapy for gastric cancer and

controversy still exist on the extend of surgery. As the stage of disease

has definitive influence on survival, earlier diagnosis is very important.

Depth of invasion, lymph node metastases, presence of distant

metastases are all found to be essential prognostic factors [2]. If the

primary lesion is removed en block with the regional lymph nodes

without leaving any residual tumor, patients might be cured [2,3].

Since the operations by McNeer et al. the role and extend of

lymphadenectomy in gastric cancer has been a point of controversy

[4,5] and has been studied in many retrospective and prospective

randomized trials.

Extensive lymph node dissection was adopted as the standard

procedure by Japanese without any randomized control trials [6–10].

The results of randomized trials by Dent and coworkers were against to

the use of more extensive dissections as the morbidity and mortality

were found to be increased without any beneficial effect on overall

survival [11–14]. When the results of specialized centers were taken

into consideration, lymph node dissection was found to have an

independent prognostic impact on survival especially in patients with

stages II and IIIA, in both Western countries and Japan [15–18].

The reported incidence of lymph node metastases in T1 cancers

(mucosa or submucosa) is 2–20% and is about 50% when the tumor

invades muscular or subserosal layers (T2) [19,20]. Based on this

information it is considered that considerably high proportion of

patients with T1 and T2 cancers are being treated with unnecessary

larger lymphadenectomy. An accurate prediction of metastases in

the regional lymph nodes will limit not only the resection but also the

extend of lymphadenectomy. For this reason, the determination of

the extend of lymphadenectomy on the basis of actual lymph node

involvement is important to reduce postoperative morbidity and

mortality rates especially in elderly patients.

SURGICAL ANATOMY OFGASTRIC LYMPHATICS

The very complex lymph nodes of stomach has been put into a very

useful classification by the Japanese Research Society of Gastric

Cancer [3]. Lymphatic vessels of the stomach follows the larger vessels

and is directed towards celiac axis. Lymph nodes located parallel to the

greater and lesser curvature (stations 1–6) classified as compartment

1 whereas, central nodes along the large vessels and celiac axis

(stations 7–11) as compartment 2. Three exemptions from this rule are

the tumors located at the cardia, the posterior wall of the proximal

fundus and tumors that grow beyond pylorus as they often have a direct

extraperitoneal lymphatic spread. Therefore, these exemptions must be

taken into consideration during lymphadenectomy.

DETECTION OF LYMPH NODES

In almost all malignant solid tumors, it is accepted that lymph node

status is one of the most important prognostic indicator of poor

survival. On the other hand, for most solid tumors a clear survival

benefit from lymphadenectomy has not been demonstrated.

The first possible sites of metastases along the route of lymphatic

drainage from the primary lesion are known as sentinel nodes. If the

sentinel node contains no metastasis then one would assume that the

tumor has not spread to the distal notes and that it might be confined to

the primary sites. In contrast to this, tumor metastasis to the sentinel

nodes indicate more advanced disease and treatment must be planned

accordingly.

In 1977 Cabanas proposed that sentinel nodes in patients with

penile cancers could be removed by limited surgery and then the

pathologic status of the sentinel node might be used to provide rational

basis for selective lymphadenectomy [21].

The sentinel node concept has initially been validated in breast

cancer and melanoma and the accuracy of prediction of nodal status by

sentinel node navigation for breast cancer is now more than 95%

[22,23]. Although it was also used in thyroid, colorectal and other

cancers as well, the feasibility and accuracy of mapping in

*Correspondence to: Dr. M. Mahir Ozmen, MD, MS, FACS, FRCS,Associate Professor of Surgery, Chief, Turan Gunes Bulvari 19. Cadde, No:9/22, Ankara 06450, Turkey. Fax: þ90-312-4286028.E-mail: [email protected]

Received 20 April 2008; Accepted 15 July 2008

DOI 10.1002/jso.21134

Published online 20 August 2008 in Wiley InterScience(www.interscience.wiley.com).

� 2008 Wiley-Liss, Inc.

gastrointestinal cancers are still unclear and controversial. There are

only a few studies available on the sentinel lymph nodes in gastric

cancer [24–31].

There are several methods to detect lymph nodes including dyes for

visual detection, radioopaque contrast agents for demonstration, and

radioactive materials for detection by gamma-camera imaging or with

hand-held detection probes.

Lymphography might be either direct—when the agent injected

directly into the lymphatic vessel—or indirect—when a tracer is

injected into the interstisium of the tissue where the lymphatic vessels

take up the material from the injection site and carry it through the flow

route [32].

Variety of dyes including indigo carmine, direct sky blue, Berlin

blue, carbon, chlorophyll, isosulfan blue, patent blue violet were used

for detection and surgical resection of nodal metastasis [33–36]. For

the detection of sentinel nodes isosulfan blue and patent blue violet are

the two most commonly used agents.

Lymphography technique using radioopaque agents was developed

by Kinmonth [37]. He first injected the patent blue violet into the

interstisium in order to make lymphatic vessels visible and then vessels

were cannulated and radioopaque dye namely thorium dioxide, was

carefully injected. This technique provided detailed radiograms of

lymphatic system.

Lymh-node scintigram was first described in 1958 by Sage and

Gozun [38]. Colloidal Au 198 was initially used and then replaced by

technetium-99m (Tc-99m) because of a better safety profile. Tc-99m

has a short half life, no significant beta emission and low dose is

required for the good detection energy. It was bound to different

pharmaceuticals including human serum albumin, antimony trisulfide,

sulfur colloid and tin colloid that determine its uptake pattern [39,40].

Lymphoscintigram may be performed for any patients to evaluate

lymph nodes, whereas sentinel node navigation has several indications

including tumor size, location, previous treatments. In common

practice, as the purpose of sentinel node navigation is to detect

micrometastasis in cases with relatively low incidence of lymph node

involvement, cases with the tumor invasion limited to muscularis

propria or submucosal layer are most suitable candidates for this

procedure. Advanced cases with large tumor and massive lymph node

involvement must be excluded in order to avoid wrong results due to

obstruction or alteration of the lymphatic drainage route.

SENTINEL NODES IN GASTRIC CANCER

Recently, sentinel node navigation surgery has been introduced

in gastrointestinal tract cancer, and ‘‘sentinel nodes’’ and ‘‘ micro-

metastasis’’ have been included in the 6th edition of the TNM

classification [41].

Currently blue dye technique and/or Technetium-99m tin colloid

are being used for identification of sentinel nodes [25–27,29–31,42–

44]. Isosulfan blue and patent blue violet are two most commonly used

agents and the timing of injection is critical for the success of this

technique as injections too early may stain the secondary nodes after

clearing sentinel nodes. Though injection site, volume and timing of

injections vary according to the authors, endoscopic submucosal

injection is commonly accepted route for administration of radioactive

tracer [45,46]. As both technique alone carries false negativity rate,

dual procedure technique has been introduced by Hayashi et al. [30].

Subserosal injection during surgery is also not a common practice as it

is difficult to localize small and superficial lesions which are not

palpable on serosal side [27]. Several hours before surgery 0.15-4mCi

Tc-99m tin colloid in a volume of 1–2 ml is injected into the

submucosal layer of the tumor with four quadrant injection using

23-gauge endoscopic needle. A hand-held gamma probe is used to

identify radioactive sentinel nodes which are defined as nodes

demonstrating more than 10-fold radioactivity in comparison to

background. Extended lymph node dissection might be performed

and after resection the absence of residual radioactivity is confirmed.

All removed lymph nodes are sent for histopathologic evaluation.

Table I shows the results of previously performed studies on sentinel

lymph node detection in gastric cancer patients [25–27,29–31,42–44].

Although the number is far from conclusion yet, the dual procedure

using dye and radioactive tracer seems better [30]. New studies with

large number of patients are currently on the way.

CURRENT TECHNIQUES FOR DETECTION:HOW TO DO IT?

Preoperative Lymphoscintigraphy

During an upper GI endoscopy a total volume of 148 MBq (2 ml)

Technetium-99m-radiolabelled filtered sulphur colloid solution

Journal of Surgical Oncology

TABLE I. The Results of Studies on Sentinel Nodes in Gastric Cancer

References

No. of

patients

Preop.

stage Method Timing Surgery

Incidence of met (%)

Sensitivity AccuracySNs Non-SNs

Kitagawa et al.

[25]

35 T1-2N0M0 99mTec tin

colloid

16 hr before surgery

and 2 hr preop.

HNs removed and

D2 LND

14.2 2.8 100% 100%

Tsioulias et al.

[26]

6 Not clear Isosulphan

blue dye

Intraoperative BNsþ regional

lymphadenectomy

16 ? 100% —

Hiratsuka

et al. [27]

74 T1-2N0M0 ICG At laparotomy SNs and D2 LND 4 1 90% 99%

Kitagawa et al.

[29]


colloid

16 hr before surgery

and 2 hr preop

HNs removed and

D2 LND

7.8 0.3 — 98.6%

Hayashi et al.

[30]


colloid and

blue dye

Tec 18 hr before

and blue dye

intraoperative

BNs, HNs and

D2 LND

22 — 100% 100%

Gretschels

et al. [31]

15 T1-3 99mTec

Nanocis

17 hr before surgery D2 LND 57 7.1 89% —

Zulfikaroglu

et al. [42]

32 T1-3 99mTec tin

colloid

2 hr before surgery D2-a LND 90 0 100% 97%

Ozmen et al.

[43]

50 T1-3 99mTec tin

colloid

48–72 hr before

surgery

D2-a LND 100 0 100% 100%

Nakahara et al.

[44]

80 T1N0M0 99mTec tin

colloid

24 hr before surgery D2 LND 4.7 ? 100% —

SNs, sentinel nodes; HNs, hot nodes; BNs, blue nodes; LND, lymph node dissection; ICG, indocyanine green.

Lymph Nodes in Gastric Cancer 477

(Lymphoscint, Amersham, UK) is injected in four quadrants around

the tumor, into the submucosal layer using endoscopic puncture needle

2–3 days before the surgery. Anterior, posterior, lateral images are

taken in 5-min intervals using a gamma camera after the injection.

The lymphatic drainage is evaluated qualitatively [43,44].

Intraoperative Detection of Sentinel Nodes Using

Radioactive Tracer

Two hours before operation, a total volume of 2 ml containing 148

MBq technetium-99m-radiolabeled, filtered sulphur colloid solution

(Lymphoscint) is injected into the submocosal layer at four quadrants

of the primary lesion with the use of a 23-gauge needle under

gastroscopy. Lymph nodes are examined by a hand-held gamma probe

(Navigator GPS; Tyco Healthcare Japan, Tokyo, Japan) during

operation as soon as possible and without significant manipulation of

the stomach or greater omentum. A sentinel node is defined by a

level of radioactivity 10 times higher than the background. After

identification of the sentinel nodes, they are sent immediately to

frozen sections for histologic examination, and then either standard

total or distal gastrectomy with extended lymphadenectomy is

performed. Before completing the operation, the absence of residual

radioactivity in the abdomen is confirmed with a hand-held gamma

probe [42].

Intraoperative Detection of Sentinel Nodes Using

Both Blue-Dye and Radioactive Tracer

One-half milliliter of 99mTc-Tin colloid (Nihon Medi-Physics Co.

Ltd., Tokyo, Japan) at a concentration of 2.5 mCi/ml is injected into

the submucosal layer at four quadrants of the primary lesion using a

23-gauge needle under gastroendoscopy 18 hr before the operation. To

wash out the residual colloid solution in the gastrointestinal tract,

purgatives are administered afterward. At the beginning of the

operation, 0.25 ml of 2% patent blue violet (CI 42045;Wako Pure

Chemical Industries Ltd., Osaka, Japan) is injected to the submucosal

layer at four quadrants of the same lesion using a 23-gauge needle

under gastroendoscopy. Lymph nodes that are stained blue within

20 min after dye injection are diagnosed as blue nodes (BNs) and

removed before starting the gastrectomy. Each individual BN is

reevaluated for radioactivity after surgery. Lymph nodes are examined

by a hand-held probe (Navigator GPS, Tyco Healthcare Japan) during

the operation, on resected specimens, or both. Background radio-

activity of 5–10 counts per second (cps) detected by the Navigator

GPS is observed in the abdominal cavity in all patients. Radioactive

lymph nodes with more than 100 radioactive counts per 10 sec are

diagnosed as hot nodes (HNs) and removed. Either BNs or HNs

are regarded as SNs [30].

HISTOLOGIC EVALUATION OFSENTINEL NODES

As the presence of cancer cells in the lymph nodes may impact the

decisions on both systemic therapy and surgery, pathologic evaluation

of lymph nodes especially sentinel nodes become more important. The

most common practice to analyze lymph nodes is first to fix them in

formalin and then embed in paraffin blocks. Although improved

isolation of lymph nodes from surrounding fatty tissues can be

accomplished by alcohol dehydration followed by xylene clearance,

this technique takes longer processing times (approximately 10 days or

more as compared to 1 or 2 days for routine processing) [47]. Limited

number of slides are made and stained with hematoxylin and eosin

(H&E). As the complete sectioning of nodes into 5 mm slides will result

in hundreds of slides per node, sections are stepped into predetermined

intervals of 0.1–0.2 mm. Immunohistochemistry may increase the

chance of identifying single cancer cell [48]. Molecular techniques

especially reverse transcriptase PCR and flow cytometry has been used

in the evaluation of metastatic cells, and also many genes have been

introduced as a marker of tumor behavior and metastases, their role in

gastric cancer are currently being investigated. The most important

benefit of studying genetic factors is to better understand the disease

pathogenesis and clinical outcome.

SIGNIFICANCE OF LYMPHADENECTOMY

The philosophy behind lymphadenectomy is that gastric cancer

often remains a locoregional disease with only local lymphatic spread.

Therefore, removal of nodes may prevent subsequent systemic spread.

Although Halstedian philosophy of lymph nodes being a barrier to

lymphatic spread was abandoned for breast cancer, the concept still

seems true for gastric cancer [49,50] as the rich arterial blood supply

and extensive lymphatic drainage create organ-specific conditions in

the treatment of gastric cancer.

The absolute number of metastatic locoregional lymph nodes (TNM

N-category) is currently considered the most reliable prognostic

indicator for patients with radically resected gastric cancer [51–55].

N-category pathological assessment can be affected by the extension of

lymph node surgical dissection, which is classically termed D1, D2,

and D3. The UICC/AJCC classification, which is the most widely used

for the staging of gastric cancer, suggests that at least 15 lymph nodes

should be examined for a correct assessment of N-category [51].

This implies that D1 lymph node dissection, which is limited to the

perigastric lymph nodes, might not guarantee an accurate staging

[51,52,55]. Nevertheless this type of lymphadenectomy is routinely

performed in several Western countries, which is supported by the fact

that D2 lymphadenectomy is associated with higher rates of post-

operative complications. This problem has been identified by Mullaney

et al. [56], who found that only 31% of cases with surgically resected

gastric cancer could be accurately assessed according to the TNM

system, suggesting the need for an improved nodal staging.

D2 lymphadenectomy was reported to be the independent

prognostic risk factor and associated with better survival in patients

with stage II and IIIA disease and also emphasized that even in the

presence of significant number of positive nodes long-term survival

was possible [15,16]. In the same way, other investigators have shown

that curative gastric resection should be performed with extensive

lymphadenectomy up to second lymph node group (D2) as a standard

procedure [57–59]. It has also been shown by Yildirim et al. [60] in a

study from Turkey that D2 dissection was associated with better overall

and disease free survival especially in Stage II and Stage IIIA.

It has recently been shown by our group that extended LND was as

effective as Japanese studies in the surgical management of advanced

gastric cancer for the western patients as well. We found that overall

survival was similar between the D2 and D3 dissection groups but

patients with T3–T4 tumors and patients with higher ratio of PLN/

TLN had better survival with D3 dissection. We have also shown that

depth of invasion (T), PLN and ratio (PLN/TLN), stage and LND were

all independent prognostic variables [61].

Despite the Japanese studies describing long-term survival in

patients with 15 or more lymph node metastases, reports from the

Western centers are mostly disappointing [62–65]. Hundahl reported

that only 1% of patients with more than 10 positive nodes survived

10 year. The rate of survival was 3% in patients with 6–10 positive

nodes [66]. Hartgrink et al. [67] conclude that there is no long-term

overall survival benefit from an extended lymph node dissection in

Western patients with gastric cancer. The associated higher post-

operative mortality offsets its long-term effect in survival. They

demonstrated that for patients with N2 disease, an extended lymph

node dissection may offer cure, but it remains difficult to identify


478 Ozmen et al.

patients who have N2 disease. Extended lymph node dissections may

be of benefit if morbidity and mortality can be reduced.

Although it is too early to comment but it seems that extended

lymphadenectomy has to be tailored and the role of the sentinel node

may be important in the decision making for disease control. On the

other hand one should always remember that the sentinel node removal

is almost entirely a diagnostic procedure which is unlikely to have any

therapeutic benefit. As a surgeon if the clear scientific evidences are

lacking, we have to continue for search in order to modify our choices

for the best of our patients.

POTENTIAL THERAPEUTIC STRATEGIESFOR LYMPH NODE METASTASIS

Clinical and biological behavior of the gastric cancer makes it a

perfect tumor for targeted therapies. Various therapies include EGFR

inhibitors, cell cycle inhibitors, metalloproteinase’s inhibitors, anti-

angiogenic agents, gene therapies and immunotherapies [68]. Thera-

pies targeted to tumors’ lymphatic compartment may inhibit metastasis

or prevent further spread based on the application time

Cancer cells escape the tumor to establish metastasis by two

primary routes including blood vessels and lymphatics. Its reasonable

to say that blocking the angiogenesis and lymhangiogenesis might

inhibit hematogenic and lymphogenic metastasis. Vascular endothelial

growth factor (VEGF) C and D and VEGFR-3 all induce angiogenesis

and lymphangiogenesis in tumors associated with lymphatic metastasis

and their expression correlates with lymph node metastasis in human

cancers [69,70]. It is actually shown by He et al. [71] that blocking the

VEGF-C and D prevents the lymphatic metastasis. Especially VEGF-D

and VEGFR-3 were recently reported to be independent prognostic

markers in gastric cancer and VEGF-D was found to be correlated with

lymphatic metastasis [72].

Currently there are more than 25 antiangiogenic drugs in trials, only

bevacizumab, a humanized monoclonal antibody to VEGF-A to be

used in combination with chemotherapy for advanced colonic cancer

[73]. Targeting the lymphangiogenic ligands (etc. VGEF-C), inhibiting

the lymphangiogenesis with soluble receptors, targeting receptors on

lymphatic endothelium (etc. VGEFR-3), using competitive ligands to

lymphangiogenic stimulators and using endogenous inhibitors of

lymphangiogenesis are all potential strategies and being used currently

for new trials [74].

CONCLUSIONS

Although studies with large number of patients from multiple

centers are currently lacking for gastric cancer, selective sentinel node

dissection is becoming standard procedure for melanoma and breast

cancer.

The presence or absence of lymph node metastasis is clinically

important for selecting the treatment strategy. D2 lymph node

dissection is still the widely accepted procedure for the treatment of

gastric cancer. We still do not know whether its use would help to

reduce the extend of lymphadenectomy, evidences from previous

reports support the use of sentinel node navigation techniques in gastric

cancer. If sentinel node navigation technique could be applied to

gastric cancer surgery, then less invasive surgery with personalized

lymphadenectomy might be possible.

REFERENCES

1. Pisani P, Parkin DM, Bray F, et al.: Estimates of the world-widemortality from 25 cancers in1990. Int J Cancer 1999;83:18–29.

2. Hermanek P, Sobin LH: UICC TNM Classification of malignanttumors. 4th edition. New York: Springer-Verlag; 1992.

3. Japanese research Society for Gastric Cancer. Japanese classi-fication for gastric carcinoma. 2nd English Edition. GastricCancer 1998;1:10–24.

4. McNeer G, Lawrence W, Ortega LG, et al.: Early results ofextended total gastrectomy for gastric cancer. Cancer 1956;9:1153–1159.

5. Gervosani JE, Taneja C, Chung MA, et al.: Biological andClinical significance of lymphadenectomy. Surg Clin North Am2000;80:1631–1673.

6. DeAretxabala X, Konishi K, Yonemura Y, et al.: Node dissectionin gastric cancer. Br J Surg 1987;74:770–773.

7. Kaibara N, Sumi K, Yonekawa M, et al.: Does extensivedissection of lymph nodes improve the results of surgicaltreatment of gastric cancer? Am J Surg 1990;159:218–221.

8. Kodoma Y, Sugimachi K, Soejima K, et al.: Evaluation ofextensive lymph node dissection for carcinoma of the stomach.World J Surg 1981;5:241–248.

9. Majima S, Etani S, Fujita Y, et al.: Evaluation of extended lymphnode dissection for gastric cancer. Jpn J Surg 1972;2:1–6.

10. Mine M, Majima S, Harada M, et al.: End results of gastrectomyfor gastric cancer: Effect of extensive lymph node dissection.Surgery 1970;68:753–758.

11. Dent DM, Madden MV, Price SK: Randomized comparison of R1and R2 gastrectomy for gastric carcinoma. Br J Surg 1988;75:110–112.

12. Dent DM, Madden MV, Price SK: Controlled trials and R1/R2controversy in the management of gastric carcinoma. Surg OncolClin North Am 1993;2:433–441.

13. Cuschieri A, Fayers P, Fielding J, et al.: Postoperative morbidityand mortality after D1 and D2 resections for gastric cancer.Lancet 1996;347:995–999.

14. Bonenkamp JJ, Songun I, Hernans J, et al.: Randomizedcomparison of morbidity after D1 and D2 dissection for gastriccancer in 996 Dutch patients. Lancet 1995;345:748–758.

15. Siewert JR, Bottcher K, Roder JD, et al.: Prognostic relevance ofsystematic lymph node dissection in gastric carcinoma. GermanGastric Carcinoma Study Group. Br J Surg 1996;80:1015–1018.

16. Siewert JR, Bottcher K, Stein HJ, et al.: Relevant prognosticfactors in gastric cancer. Ten year results of the German GastricCancer Study. Ann Surg 1998;228:449–461.

17. Volpe CM, Koo J, Miloro Sm, et al.: The effect of extendedlymphadenectomy on survival in patients with gastric carcinoma.J Am Coll Surg 1995;181:56–64.

18. Kodera Y, Yamamura Y, Torii A, et al.: Postoperative Staging ofgastric carcinoma. Scand J Gastroenterol 1996;31:476–480.

19. Sasako M, McCulloch P, Kinashita T, et al.: New method toevaluate the therapeutic value of lymph node dissection for gastriccancer. Br J Surg 1995;82:346–351.

20. Miwa K, Miyazaki I, Sahara H, et al.: Rationale for extensivelymhadenectomy in early gastric carcinoma. Br J Cancer 1995;72:1518–1524.

21. Cabanas RM: An approach for the treatment of penile carcinoma.Cancer 1977;39:456–466.

22. Borgstein PJ, Meijer S, Pijpers R: Intradermal blue dye to identifysentinel lymph node in breast cancer. Lancet 1997;349:1668–1669.

23. Veronesi U, Paganelli G, Galimberti V, et al.: Sentinel-nodebiopsy to avoid axillary dissection in breast cancer with clinicallynegative lymph-nodes. Lancet 1997;349:1864–1867.

24. Maruyama K, Sasako M, Kinoshita T, et al.: Can sentinel nodebiopsy indicate rational extend of lymphadenectomy in gastriccancer surgery? Langenbeck’s Arch Surg 1999;384:149–157.

25. Kitagawa Y, Hirofumi F, Mukai M, et al.: The role of the sentinellymph node in gastrointestinal cancer. Surg Clin North Am 2000;80:1799–1809.

26. Tsioulias G, Wood TF, Morton DL, et al.: Lymphatic mapping andfocused analysis of sentinel lymph nodes upstage gastrointestinalneoplasms. Arch Surg 2000;135:926–932.

27. Hiratsuka M, Miyashiro I, Ishikawa O, et al.: Application ofsentinel node biopsy to gastric cancer surgery. Surgery 2001;129:335–340.



28. Yasuda S, Shimida H, Ogoshi K, et al.: Preliminary study forsentinel lymph node identification with Tc-99m tin colloid inpatients with esophageal or gastric cancer. Tokai J Exp Clin med2001;26:15–18.

29. Kitagawa Y, Fujii H, Mukai M, et al.: Radio-guided sentinel nodedetection for gastric cancer. Br J Surg 2002;89:604–608.

30. Hayashi H, Ochiai T, Mori M, et al.: Sentinel lymph nodemapping for gastric cancer using a dual procedure with dye andgamma probe-guided techniques. J Am Coll Surg 2003;196:68–74.

31. Gretschel S, Bembenek A, Ulmer CH, et al.: lymphatic mappingand sentinel lymph node biopsy in gastric cancer. Chirurg 2003;74:132–138.

32. Krag ND: Minimal access surgery for staging regional lymphnodes: The sentinel node concept. Curr Problems Surg 1998;35:951–1018.

33. Eichner E, Goldberg I, Bove ER: In vivo studies with direct skyblue of the lymphatic drainage of the internal genitals of women.Am J Obstet Gynecol 1954;67:1277–1287.

34. Enquist IF, Block IR: Rectal cancer in the female: Selectionof proper operation based upon anatomic studies of rectallymphatics. Prog Clin Cancer 1966;2:73–85.

35. Nopajaroonsri C, Simon GT: Phagocytosis of colloidal carbon in alymph node. Am J Pathol 1971;65:25–42.

36. Averette HE, Hudson RC, Ferguson JH: Lymphangioadenog-raphy: Applications in the study and management of gynecologiccancer. Cancer 1964;17:1093–1107.

37. Kinmonth JB: Lymphangiography in clinical surgery andparticularly in the treatment of lymphoedema. Ann R Coll SurgEngl 1954;300:14–15.

38. Sage H, Gozun BV: Lymphatic scintigrams: Method for studyingfunction of lymphatics and lymph nodes. Cancer 1958;11:200–203.

39. Bergqvist L, Strand S-E, Persson BRR: Particle sizing andbiokinetics of interstitial lymphoscintigraphic agents. Semin NuclMed 1983;13:9–19.

40. Hung JC, Wiseman GA, Wahner HW, et al.: Filtered technetium-99m- sulfur colloid evaluated for lymphoscintigraphy. J Nucl Med1995;36:1895–1901.

41. Sobin LH: TNM: Evolution and relation to other prognosticfactors. Semin Surg Oncol 2003;21:3–11.

42. Zulfikaroglu B, Koc M, Ozmen MM, et al.: Intraoperativelymphatic mapping and sentinel lymph node biopsy usingradioactive tracer in gastric cancer. Surgery 2005;138:899–904.

43. Ozmen MM, Zulfikaroglu B, Kucuk NO, et al.: Lymphoscintig-raphy in detection of the regional lymph node involvement ingastric cancer. Ann R Coll Surg Engl 2006;88:632–638.

44. Nakahara T, Kitagawa Y, Yakeuchi H, et al.: Preoperativelymphoscintigraphy for detection of sentinel lymph node inpatients with gastric cancer-initial experience. Ann Surg Oncol2008;15:1447–1453.

45. Dauway EL, Giuliano R, Pendas S, et al.: Lymphatic mapping: Atechnique providing accurate staging for breast cancer. BreastCancer 1999;6:145–154.

46. Haigh PI, Hsueh EC, Giuliano AE: Sentinel lymphadenectomy inbreast cancer. Breast Cancer 1999;6:139–144.

47. Hida J, Mori N, Kubo R, et al.: Metastases from carcinoma of thecolon and rectum detected in small lymph nodes by the clearingmethod. J Am Coll Surg 1994;178:223.

48. Krag DN, Weaver DL: Pathological and molecular assessment ofsentinel lymph nodes in solid tumors. Semin Oncol 2002;29:274–279.

49. Foster RS: The Biological and Clinical significance of lymphaticmetastases in breast cancer. In: Lymph nodes in SurgicalOncology. Edited by Cady B and Foster R. Surgical OncologyClinics of North America 1996;5:79–104.

50. Sasako M: Surgical Management of Gastric Cancer: The JapaneseExperience. In: Daly JM, Hennessy TPJ, Reynolds JV, editors.Management of upper gastrointestinal cancer. UK: WB Saunders;1999; pp:107–123.

51. Marchet A, Mocellin S, Ambrosi A, et al.: The prognostic value ofN-ratio in patients with gastric cancer: Validation in a large,multicenter series. Eur J Surg Oncol 2008;34:159–165.

52. Liu C, Lu P, Lu Y, et al.: Clinical implications of metastatic lymphnode ratio in gastric cancer. BMC Cancer 2007;7:201–208.

53. Tangoku A, Seike J, Nakano K, et al.: Current status of sentinellymph node navigation surgery in breast and gastrointestinal tract.J Med Invest 2007;54:1–18.

54. Saito H, Fukumoto Y, Osaki T, et al.: Prognostic significance ofthe ratio between metastatic and dissected lymph node (n ratio) inpatients with advanced gastric cancer. J Surg Oncol 2008;97:132–135.

55. Persiani R, Rausei S, Biondi A, et al.: Ratio of metastatic lymphnodes: Impact on staging and survival of gastric cancer. Eur J SurgOncol 2007;10:1–6.

56. Mullaney PJ, Wadley MS, Hyde C, et al.: Appraisal ofcomplicance with the UICC/AJCC staging system in the stagingof gastric cancer. Union International Contra la Cancrum/American Joint Committee on Cancer. Br J Surg 2002;89:1405–1408.

57. Fatouros M, Ziogas D: Controversy in the treatment of gastriccancer. Ann Surg Oncol 2008;15:1795–1797.

58. Kodera Y: The beginning of a new era: East meets West morecomfortably regarding lymphadenectomy for gastric cancer-Japanwill finally drop the surgery-alone arm in its pursuit of amultimodal treatment strategy. Gastric Cancer 2007;10:69–74.

59. Sasagawa T, Solano H, Vega W, et al.: The effectiveness ofextended lymph node dissection for gastric cancer performed inCosta Rica under the supervision of a Japanese surgeon: Acomparison with surgical results in Japan. Am J Surg 2008;195:53–60.

60. Yildirim E, Celen O, Berberoglu U: The Turkish experience withcurative gastrectomies for gastric carcinoma: Is D2 dissectionworthwhile? J Am Coll Surg 2001;192:25–37.

61. Ozmen MM, Moran M, Zulfikaroglu B, et al.: Prospectiverandomized trial comparing D2 vs D3 dissection for advancedgastric cancer. Ann Oncol 2007;18:vii56 (abstract).

62. Ichitkura T, Tomimatsu S, Okusa Y, et al.: Comparison of theprognostic significance between the number of metastatic lymphnodes and nodal stage based on their location in patients withgastric cancer. J Clin Oncol 1993;11:1894–1900.

63. Isozaki T, Okajima K, Kawashima Y, et al.: Prognostic value ofthe number of metastatic lymph nodes in gastric cancer withradical surgery. J Surg Oncol 1993;53:247–251.

64. Bonenkamp JJ, Hermans J, Sasako M, et al.: Extended lymph-node dissection for gastric cancer. Dutch Gastric Cancer Group. NEngl J Med 1999;340:908–914.

65. Cuschieri A, Weeden S, Fielding J, et al.: Patient survival after D1and D2 resections for gastric cancer: Long-term results of theMRC randomized surgical trial. Surgical Co-operative group. Br JCancer 1999;79:1522–1530.

66. Hundahl SA, Phillips JL, Menck HR: The national cancerdatabase report on poor survival of U.S. gastric carcinomapatients treated with gastrectomy, ed 5. American joint committeeon cancer staging, proximal disease and ‘the different disease’hypothesis. Communication. The American College of SurgeonsCommission on Cancer and The American Cancer Society.Cancer 2000; 88(4) 921–932.

67. Hartgrink HH, van de Velde CJH, Putter H, et al.: Extended lymphnode dissection for gastric cancer: Who may benefit? Final resultsof the randomized Dutch Gastric Cancer Group trial. J Clin Oncol2004;22:2069–2077.

68. Khan FA, Shukla AN: Pathogenesisi and treatment of gastriccarcinoma: ‘‘An up-date with brief review’’. J Cancer Res 2006;2:196–199.

69. Stacker SA, Caesar C, Baldwin ME, et al.: VEGF-D promotes themetastatic spread of tumor cells via the lymphatics. Nat Med2001;7:186–191.

70. Alitalo K, Carmeliet P: Molecular mechanisms of lymphangio-genesis in health and disease. Cancer Cell 2002;1:210–227.


480 Ozmen et al.

71. He Y, Kozaki K, Karpanen T, et al.: Suppression of tumorlymphangiogenesis and lymph node metastasis by blockingvascular endothelial growth factor receptor-3 signaling. J NatlCancer Inst 2002;94:819–825.

72. Juttner S, Wissmann C, Jons T, et al.: Vascular endothelial growthfactor-D and its receptor VEGFR-3: Two novel independent

prognostic markers in gastric adenocarcinoma. J Clin Oncol 2006;24:228–240.

73. Slevin M, Payne S: New treatments for colon cancer. BMJ2004;329:124–126.

74. Zwaaans BMM, Bielenberg DR: Potential Therapeutic Strategiesfor lymphatic metastasis. Microvascular Res 2007;74:145–158.



Documents

Lymph nodes in gastric cancer