Principles of Surgical Radicality in the Treatment of Gastric Cancer

UPDATE ON SURGICAL ONCOLOGY IN EUROPE

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PRINCIPLES OF SURGICAL RADICALITY IN THE TREATMENT OF GASTRIC CANCER Federico Bozzetti, MD

Surgery for gastric cancer, as for many other solid tumors, is based on an apparently simple principle: removal of the entire tumor within clear margins of transection. Although it is obvious that cutting in tumoral tissue (i.e., obtaining resection margins involved by the tumor microscopically [Rl] or macroscopically [R2]) almost always results in a local relapse of the disease, we have no guarantee that in achieving tumor-free resection margins we succeed in curing the patient. Why is this? The fact is that we sometimes erroneously believe that we have achieved free margins while the disease remains present beyond these margins because of the discontinuous spread of the tumor, and sometimes-when these margins are far from the primary lesion or are extraregional (typically the distant lymph nodes)--they merely indicate the presence of a systemic malignancy. These distant neoplastic foci do not govern the prognosis of the disease, because a resection, which encompasses them just to achieve a safe clearance, does not cure the patient. Curative surgery of the stomach lies somewhere between the two extremes: avoidance of involved margins of resection on the stomach without extension of the lymphadenectomy to these remote lymph nodes which, if involved, indicate the presence of a systemic disease that can no longer be affected either by their removal or by their persistence. The major criteria involved in choice of surgical strategy are the T component and the location of the tumor in the stomach. ASSESSMENT OF THE T STAGE

The Tumor-Node-Metastasis (TNM) classification is used throughout the world to define tumor penetration into the gastric wall (Table 1). From the International Gastric Cancer Association, Milan, Italy

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Table 1.TNM CLASSIFICATION (UlCC 1997)-DEFINITIONS Primary Tumor

TX TO TIS

Regional lymph nodes NX NO N1 N2 N3

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ: intraepitelial tumor without invasion of the lamina propria Tumor invades muscularis propria or submucosa Tumor invades muscularis propria or subserosa Tumor invades serosa (visceral peritoneum) Tumor invades adjacent structures Regional lymph nodes cannot be assessed No regional lymph nodes metastasis Metastases in 1 to 6 lymph nodes Metastases in 7 to 15 lymph nodes Metastases in > 15 lymph nodes

The regional lymph nodes are the perigastric ones along the lesser and greater curvatures, the nodes along the left gastric, common hepatic, splenic and coeliac arteries, and the hepatoduodenal nodes.

Fortunately, assessment of the T stage through endoscopy is quite accurate, at least in terms of differentiating early gastric cancer (EGC) from more advanced cancers. In Japan, endoscopists are trained to estimate the depth of tumor invasion (mucosa, submucosa, or deeper) by closely examining the color and stiffness of the lesion and the shape of the converging folds while adjusting the volume of air in the stomach. Following this training, an expert endoscopist is able to distinguish an EGC from a deeper tumor in 90%of patients using routine endoscopy alone.Io5 The European literature shows that the general accuracy of endoscopic ultrasonography in correctly assessing the pT category ranges from 70% to 90%.23,33,77,82 The concordance between uT1 and pT1 and uT3-uT4 and pT3-pT4 was 73.6%to 85.7%and 84.9% to 91.1%,respectively, in two values that are higher than the 20%to 56% recent Western e~periences,4~,~~ reported in the Japanese literature, using the CT scan.37,52, 84 ASSESSMENT OF THE N STAGE

With regard to the scope of the lymphadenectomy, we do not currently have any direct diagnostic means to know a priori that lymph nodes zi-2 metastatic: henceworth bFln= 0 .p-nr:& ------. Intraoperative lymphatic mapping is in its infancy; Xu et allz9injected methylene blue dye in the patients and found that this facilitated the retrieval of positive lymph nodes. Several hours before surgery Kitagawa et a1@injected endoscopically 0.15 to 4 mCi of 99mTc-Sn colloid in 36 patients, subsequently identifying the sentinel node in 97%of cases. Although the frequency of lymph node involvement was significantly higher in sentinel versus nonsentinel nodes (7%versus 0.3%).It appears, ---'

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however, that it is too early to apply the sentinel node biopsy for reducing the extent of lymphadenectomy because of frequent s k i p metastases; in fact, sentinel nodes have been detected in 40% of cases in the second lymph node level and sometimes in the third compartment as we11.81 a result, the volume of dissection is determined based on the probability of involvement of the lymph nodes and on the knowledge of the natural history of the gastric cancer and of the outcome of patients with varying risks. As to the probability of lymph nodes, a computer program was developed by Maruyama's on the basis of 4302 patients operated on at the National Cancer Center Hospital in Tokyo, in which eight variables were known: gender, age, macroscopic type, location, position, diameter, World Health Organization (WHO) histologic type, and depth of wall invasion. The predictive ability of the computer program for lymph node metastases has been validated both by a German study7 and an Italian in the latter, the areas under the curve had a mean value of 0.856.

SURGICAL MANAGEMENT OF EARLY GASTRIC CANCER ('61) In 1962 EGC was defined as an adenocarcinoma confined to mucosa or submucosa, irrespective of lymph node i n v o ~ ~ e r n eThe ~ t clini.~~ copathologic features of the disease and its prognostic significance have been investigated in-depth in Japan in studies that have sometimes included over 1000 p a t i e n t ~ . ~ ~ The choice of surgical procedure in Western countries is based mainly on the following four considerations: 1. It is difficult to accept the results of the conservative surgery of the Japanese authors because there is some discrepancy in the diagnosis between Eastern and Western pathologists; some differentiated mucosal lesions diagnosed as carcinoma in Japan have been defined as dysplasia in the West.",lo8 2. In the West, an EGC diagnosis is rarely made prior to surgery. In the Birmingham study,@only three of 15 EGCs were macroscopically diagnosed as cancer at the initial endoscopy. However, such recognition is likely to increase with the increasing use of echoendoscopy. 3. Survival following conventional subtotal gastrectomy for EGC is similar to that of the general population (Fig. 1). The new conservative surgical approaches must therefore be Compared with a time-honored procedure that is well tolerated and associated with a life that is normal both in duration and in quality. 4. Only a transabdominal approach enables the surgeon to perform a lymphadenectomy. Although the need for a lymphadenectomyin all types of EGC is questionable, experts have yet to establish welldefined criteria for avoiding it.

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Time (y) Figure 1. The survival of patients operated on for early gastric cancer (EGC) (dashedline) is not different (P = not significant) from that of a sex- and age-matched population from Northern Italy (solid line) without EGC. (From Bozzetti F, Bonfanti G, Mariani L, et al: Early gastric cancer: Unrecognized indicator of multiple malignancies. World J Surg 24:583-587, 2000; with permission.)

Moreover, it is well known that EGC is associated with an increased risk of other primary malignancies, ranging from 7.6% according to the Japanese a ~ t h o r sto~ 34.3% ~ , ~ ~in some European series.13,43,74 We might speculate that the continuous nitrosification by bacteria in the gastric stump produces carcinogenic N-nitroso corn pound^^^^^^^'^^^'^^ with different extragastric distant target organs. Looked at from this standpoint, a wide resection of the stomach could be more protective than a limited one. Finally, it is worth noting that frequency of metachronous recurrences in the stomach ranges from 2.5% to 11%following endoscopic treatment.4,60It has recently been shown that 30% of patients with recurrent disease following endoscopic treatment presented a microsatel... iite ii;st&i;i:y, whereas none of the ~ z t i e ~with l t ~ nonrecurrent disease did so.60 The Laparotomic Approach

Gastrectomy is the treatment of choice for EGC in Japan, where it is applied in about 80% of cases, and in Europe, where the outcomes of surgery are reported as being comparable with Japanese results. The

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associated lymphadenectomy may be a D2 or a Dl NQ - 7 (left gastric arter~ nodes). EGCs in the proximal stomach, a total gastrectomy i S usually performed, without dissection of the splenic hilar nodes, w h i c h are seldom involved by tumors. In an attempt to preserve the function of the stomach, Qwever, modified gastrectomies have recently been devised. Currently th pyloruspreserving gastrectomy is recommended for EGC of the Q 'ddle stomach, since this distal two-thirds gastrectomy preserves a p y l ~ r cuff i ~ of 2 cm, the hepatic and pyloric branches of the vagal nerve, and t h e suprapyloric nodes (No. 5), which are involved very rarely.64 For EGC in the proximal third of the stomach, a proximal with jejunal pouch interposition with or without saving t h e gastrectomy vagal nerves has been proposed in some institution^.^^^'^^ More conservap resections include the segmental gastrectomy for midstomach EGC, kith preservation of the hepatic and pyloric branches with40 or without92 the perigasof the Latarjet branch and with lymphadenectomy limited t, preservation tric nodes close to the resected portion. For intramucosal EGC smaller than 4 cm, a local Wedge resection through laparotomy or laparoscopy has been proposed b S.' Seto"' and Ohgami.9' Japanese s ~ r ~ e o n shave ~.'~ also ~ reported satisfying su rgical results with the laparoscopy-assisted Billroth I gastrectomy or 1 aparoscopic wedge resection.

or

Endoscopic Mucosal Resection The endoscopic mucosal resection (EMR) procedure c Onsists of the injection of saline to lift the mucosa and the subsequent res %ion for the elevated portion leaving an artificial ulcer based on the muscularis propria. It is a primarily diagnostic process which may be accepted as a definitive treatment if the subsequent histologic examination of the resected specimen satisfies the following conditions: intramucosaltumor of the elevated type (I or IIa) or depressed type (IIc); smaller than 2 cm; With out ulcer or ulcer scar; and histologically classified as well or moderat "Y differentiated adenocar~inoma.'~~

TransgastrostomalEndoscopic Resection This is a useful technique for posterior wall lesions for tomies and full-thickness excisions. It involves a small midy muCOSecIne incision, suture of the anterior gastric wall to the skin, and an anterio gastrotomy. Thereafter an endoscopic resection can be performed.13'

Lymphadenectomy Because the tumor is completely confined to the gastric all, the only possibility of local spread is through the lymphatic route. Th Prevalence

of nodal metastases is about 3% or less in mucosal cancers and approaches 20% when the tumor invades the submucosa. The lymphatic spread may not be sequential and jumping metastases to extraperigastric lymph nodes have been reported h i s t ~ l o g i c a l l yMoreover, . ~ ~ ~ ~ ~ with special examination techniques such as multisection of nodes or immunohistochemical staining, the prevalence of micrometastases may increase c ~ n s i d e r a b l y .Micrometastases ~~,~~ have been reported in 19%of patients with mucosal gastric cancer and even in 8% of patients with EGC of the mucosa less or equal to 1 In conclusion, in everyday practice difficulty in differentiating EGC from advanced cancer, intramucosal from submucosal cancer, unpredictability of nodal metastases and uncertainty of the biological meaning of micrometastases, make partial or total gastrectomy + Dl or Dl-D2 lymphadenectomy a reasonable option for the majority of good-risk patients with EGC. Until today, this type of surgical procedure has continued to represent the gold standard operation, even if recent experience has demonstrated the feasibility and the safety of the laparoscopically assisted gastrectomy with lymph node dissection.' SURGICAL MANAGEMENT OF ADVANCED CANCER Surgery of the Organ in T2-T3 Tumors

The extent of resection on the stomach is dictated primarily by the knowledge of the length of the microscopic intramural spread of the tumor beyond the clinically appreciated boundaries of the tumor. In some critical regions (pyloric or subcardial tumors) a compromise has to be achieved between the desirable length of clearance and the need to avoid an overly extended or multiorgan resection. In recent decades some European s t u d i e ~ 'have ~ , ~ ~defined that the conditio sine qua non for achieving a proximal clear margin of transection was to maintain a 6-cm length of clearance from the upper border of the tumor, measured during lapar~tomy'~ (Fig. 2). In T2 tumors a 3-cm clearance was deemed equally satisfying to avoid involved margins. Tumors of the Distal Half of the Stomach Tn line with the previously mentioned criteria, a tumor in the midstomach could be resected wiih ihc same radic.?!ity !as reeards the margins of transection) by performing either a total gastrecto&y or a subtotal one, provided that at least 6 cm of clearance could be maintained. The truth of this hypothesis was demonstrated by a large Italian multicenter randomized clinical trialz5that reported the same long-term survival in patients undergoing total and subtotal gastrectomies for cancer of the middle and distal stomach (Fig. 3). This study definitively confirmed the data of a previous randomized clinical trial comparing the two procedures in cancer of the gastric a n t r ~ m . ~ ~

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Histologically pos. margins

Figure 2. The chance of having the proximal gastric margin involved by the tumor varies depending on the distance of the transection line from the upper limits of the tumor. A safe distance to achieve free-margin is at least 6 cm in pT3-pT4 lesions. For pT1-pT2 categories the margins of clearance may be curtailed by half.

Since in the Italian study,16 as in many others, postoperative morbidity was mainly dependent on splenectomy at the multivariate analysis-and this occurred more frequently with total than with subtotal gastrectomy (18% versus 5%)-and the nutritional status too is more affected by total than by subtotal gastre~tomy,'~ it appears that total gastrectomy is only indicated when it is necessary to resect the cardia in order to achieve 6 cm of clearance. Indeed, for the majority of these gastric cancers a subtotal gastrectomy is adequate. Tumors of the Proximal Stomach

Gastric cancer now tends to be more proximal in location and to affect young people more frequently. These tumors may involve the fundus or the great curvature, but most are subcardial. This means that they infiltrate the esophagogastric

Months Figure 3. There is no statistically significant difference in survival between patients randomized to subtotal (SG) or total (TG) gastrectomy for a tumor of distal and midstornach. (Adapted from Bozzetti F, Marubini E, Bonfanti G, et al: Subtotal versus total gastrectomy for gastric cancer: Five-year survival in a multicenter randomized Italian trial. Ann Surg 230:170-178, 1999; with permission.)

junction from below and meet the original criteria of Siewert, who defined the type I11 tumor of the esophagogastric junction as "cardia adenocarcinoma extending to the stomach, with the center lying 2 to 5 cm below the esophagogastricjunction." Typically these tumors are found more frequently in men; they usually belong to the intestinal variety as defined by Lauren, and have a high prevalence of G3/G4 differentiation. The tendency to invade the esophagus ranges from 3.7% in the Japanese experience13' to 26%to 63%in many Western surgical series.53,83,100, lo9, The risk factors for esophageal invasion are the presence of Borrmann IV type or infiltrative tumors, linitis plastica, or diffuse type pT3-pT4 or N+ stages or lesions exceeding a maximum 5-cm diameter.83,94 Because an important route of tumor spread is the intramural one, surgeons should be aware of the risk of having proximally involved margins when they resect tumors of the proximal stomach close to the subcardial area. In 1980 Papachristou et aP9 reported that only by maintaining .c. .. .. .:. 11-.. L. "..-A.". . ....-L,== th-n 6 c- CE , ~12ropen~ he -- -- -arc+-O^-.cf -" sure of not having a histologically positive transection margin. It is worth noting that these measures were obtained during an intraoperative assessment and therefore do not need to be adjusted for retraction of the esophagus once the specimen has been resected and delivered to the pathologist. If 4.1 to 6 cm of clearance is maintained, there is a 9% risk of positive margin and the risk approximately doubles if the length of clearance is shortened by 2 cm. LAkuci-Gu --i.3-. ,.a

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Some Japanese author^^^,'^^ have suggested modulating the length of the margins of clearance by some histopathologic features; they suggest a clearance of 2 cm for the localized type,1342.5 cm for the well4 cm for the infiltrating type,134and differentiated or Borrmann 1-11 > 5 cm for the poorly differentiated or Borrmann 111-IV type.93 In conclusion, if the tumor appears to be localized, noninfiltrating, and with an esophageal involvement of less than 2 cm, the entire surgical procedure may be performed using an abdominal transhiatal approach which allows an esophageal transection at 2-2.5 cm from the cranial edge of the tumor. For tumors that are infiltrating, poorly differentiated, or Borrmann 111-IV, a longer margin of clearance, and consequently a right thoracotomy may be required. The extension of the tumor in the esophagus for a length exceeding 3 cm is not an indication for extended thoracic surgery, since no long-term survival has been reported with such an aggressive tumor.'34 Recent experience with preoperative endoscopic ultrasonographyZ8 has proven extremely accurate in distinguishing between tumors with an esophageal invasion more or less than 2 cm. In contrast, intraoperatively frozen section examinations have proven to be deceptive, with an unacceptable rate of 9% to 21% of false-negative finding^.^^,'^^ Both intraoperative immunostaining techniques of margins and in situ sonography have met with little success. Surgical Management of T4 Tumors Irrespective of the location of the tumor in the stomach, if the lesion involves one or more neighboring organs, they should be removed along with the stomach, provided that this combined resection allows a RO/R1 procedure. In fact, it has been reported that in such circumstances the oncologic outcome is more dependent on the N stage and location of the tumor than on the T stage." Because it is well known16 that the extension of surgery to adjacent organs is associated with higher postoperative morbidity than the nonextended one, however, the decision whether to resect or not should be made with caution. Unfortunately clinically suspected involvement of an adjacent organ is confirmed at the subsequent histopathologic examination in 33%to 57% of cases18, 47,71,88,107 only, Table 2 reports the 5-year survival of patients undergoing a gastrectomy extended to the neighboring organs. It should be noted that these reports present a very selective series of patients and that, except for the expertise of the individual surgeon, quite often there is no reliable criteria for determining in which individuals the extended operation prove to be successful or futile. In conclusion, we know that extended surgery may be curative for some patients, but we do not know for which patients.

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Table 2. FIVE-YEAR SURVIVAL AFTER RESECTION EXTENDED TO THE CONTIGUOUS STRUCTURES Author

Mesocolon

Colon

Pancreas

Spleen

Liver

Maruyama7' Korenaga'j9 Korenaga70 Adachi' Shiun4 Koga'j6 Koga'j8 TakagiIz1 SugimachiU9 Sato'07 Takaha~hi'~~ Yonem~ra'~~ O~achi~~ Shchepotinn2 * = 4-year sunrival; b = body and tail; h = head.

LYMPHADENECTOMY Classificationand Definition The issue of the scope of a lymphadenectomy is confused, in terms of terminology and substance. The original Japanese classification established in 1962 by the Japanese Research Society for Gastric Cancer relied on the anatomic site of the lymph nodes depending on the primary location of the tumor in the stomach. The three levels of lymph node compartments were identified on the basis of the frequency and the sequence of the nodal in~olvernent.~~ This classification had some advantages: it was anatomic and precise, and it allowed a comparison among different centers using a common language. There were several disadvantages, however.

1. Because it is somewhat complicated, cumbersome, and timeconsuming, and requires strong cooperation among surgeons and pathologists, it was accepted in only a few institutions outside of japari. 2. When D l and D2 were prospectively compared in an excellent randomized clinical trial with a quality control, it appeared that it was quite difficult, even under a controlled investigation, to standardize the magnitude of lymph node dissecti~n.~ In fact, a high frequency of protocol violations was reported, including 22% to 23% of contamination (i.e., the removal of an extra number of nodes not required by the protocol) and 81.5% of noncompliance (i.e.,

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incompleteness of dissection in at least one group of nodes belonging to the tier to be removed). 3. There are some lymph node stations that may not in fact contain nodes (i.e., left paracardial, suprapyloric, splenic hil~m).~O 4. When recommending the D2 lymphadenectomy, the same Japanese authors maintained that the removal of some I1 level lymph nodes (such as the left paracardial and the splenic hilum in tumors of the mid-stomach or the supra- and infrapyloric nodes in tumors of the upper third) was optional. In conclusion, even when the literature refers to the Japanese classification to define Dl or D2 lymphadenectomics, the scope of the dissection is ill-defined and appears to be poorly reproducible. In an attempt to simplify the Japanese classification, the 1978 edition of TNMIZ6defined the I level as the perigastric nodes and the I1 level compartment as including the lymph nodes along the major vessels (left gastric, splenic, coeliac, common hepatic artery), irrespective of the location of the primary tumor, and also the perigastric nodes placed at a distance higher than 3 cm from the primary tumor. The limitation of this classification is the fact that the anatomic position and distance of the perigastric nodes ( 5or > 3 cm) may change during the dissection of the organ14and that there is no correspondence between the definition of I and I1 levels between the Japanese and the TNM classifications, and consequently in the definition of the Dl and D2 procedures. After a decade the TNM classification was further simplified: all perigastric lymph nodes, irrespective of their distance from the primary tumor, were defined as I level, and those along the great vessels as the I1 level. Depending on the number of metastatic nodes, 1 to 6, 7 to 15, and more than 15, but irrespective of their belonging to the I or I1 level, nodal involvement was classified as classes N1, N2, and N3. This classification was promptly accepted by the Japanese authors36,50,54,59,65 who acknowledged the strong prognostic capacity of this staging system. It required that at least 15 lymph nodes be dissected to stage the disease properly. This change in N classification was accompanied by a change in terminology regarding the extent of lymphadenectomy. Initial anatomic studies of the number of lymph nodes counted in the upper abdomen of corpses with reference to a D2 lymphadene~tomy'~~ suggested that a D2 dissection in the Japanese style should include at least 27 lymph nodes. In contrast, a Dl d i s s e c t i ~ n would ' ~ ~ include about 15 lymph nodes. These findings were further corroborated by a series of clinicopathologic studies which showed that the mean number of lymph nodes were 17 and 31 in Dl and D2 dissections, respectively (Table 3). These studies, therefore, along with the change in the TNM classification, prompted the adoption of a new terminology in Western countries, one that defined Dl as a lymphadenectomy including the perigastric nodes or a number of 15 lymph nodes, and D2 as one including 25 or more lymph nodes.

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Table 3. NUMBER OF RETRIEVED LYMPH NODES ACCORDING TO THE TYPE OF LYMPHADENECTOMY USING THE JAPANESE CLASSIFICATION Mean Number of Lymph Nodes

Author

No. of Pts,

Dl

02

Wagt~er"~ Siewertn9 Soga1'* Adachi2 I~hikura~~ ManzoniZ9 Bonenkampg mean

Current Approach: The So-Called "Over D l " Lymphadenectomy

At present, our recommendation for the volume of lymph node dissection is based on the following three points. 1. Although a large retrospective series (a few thousand cases) of Western and Japanese patient^'^,^^, lZ8showed no advantage in survival for D3 versus D2 and D2 versus Dl lymphadenectomies, I believe that these large reviews are more useful for indicating the median outcomes of national or multi-institutional surgical policies than for comparing different surgical techniques (i.e., Iymphadenectomies of different extents). 2. The few randomized clinical trials comparing two levels of dissection are weakened either by the small number of patients in~luded~~ or, ~ by~ the , ' ~ practical ~ difficulties involved in performing the two procedures without violating protocol (contamination or poor ~ o m p l i a n c e ) .As ~ , ~a~matter of fact, these trials probably compared two procedures which could be defined in Japanese jargon as Dl-D1.5 versus D1.5-D2 dissections. They failed to demonstrate an oncologic advantage for the extended procedure, even if a recent retrospective reanalysis of the Dutch trial did show a benefit in survival in some N+ categories using the new TNM classification (van de Velde, personal communication April 5,2000). 3. There are some report^^^,^^,"^ that claim improved survival, without excessive surgical mortality, in patients who undergo an ex-. tended iiissection." "Ethoilgh the rc?;,-i7;5pecti.,ie cornr.> r-A:"-*. r: =nn ef these surgical series is often biased by a variety of factors, especially when the comparison is stratified by stage of disease (whose accuracy is affected by the surgical procedure itself-the so-called Will Rogers p h e n ~ m e n o n ~the ~ ) ,fact that some patients with metastases in the extraperigastriclymph nodes survive longterm after an extended dissection is an implicit demonstration of the curative potential of wide lymphadenectomy in some cases.

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I believe that an adequate lymphadenectomy s h o u l d meet the double task of staging the disease accurately and providing th best chance of cure. In our experience with 615 patients participating ih randomized controlled trial (RCT), the predicted p r o b a b multicentric creased up to the retrieval of about 20 to 25 lymph nodes, *'lity N+ inn d became stable thereafter (Fig. 4). This number is higher than that of 1 5 reported by other author^.^^,^^^,"^ Furthermore, analysis lymph nodes tic impact of the number of resected lymph nodes e v a Of l ~ the prognosa t e d as continuous variables has shown that extending the dissection to of 25 lymph nodes has a beneficial effect which remains st a maximum 5). able thereafter (Fip. 0 Returning to the initial definition of radicality, it w o b l the involvement of up to 20 to 25 lymph nodes can b e 4 appear that a governor and not a mere predictor of the oncologic o u t as Come. Beyond this number, however, the involvement of nodes has a mePely prognostic meaning, with a more extended dissection no longer affectsis. We prefer to define this wide dissection as an over D llh6 1 the prognotomy. In fact, it would be incorrect to define it as a D2, as t h - Ymphadenecthe Japanese definition with its attendant topographic imp1 -IS would recall ?Cations.Moreover, it is more extended than any Dl procedure, because 't the perigastric lymph nodes and removes more than 15l y m encompasses Ph nodes.

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20

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40

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Resected Lymph Nodes

Figure 4. The probability of staging lymph node as N+ changes according t number of the retrieved nodes, up to an overall number of 20-25. Thereafter, a plateau0 suggestion is that for a proper staging, about 20 to 25 lymph nodes should '@ached.The examined. removed and

2

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High risk category

0

Low risk category

Resected Lymph Nodes

Figure 5. Survival probability changes according to the scope of lymphadenectomy.The dissection of an extra number of lymph nodes beyond 20 to 25 does not appear to confer further benefit to the patient in the groups of patients that are defined as low risk (i.e., nonextended surgery, pT1 stage, 1 metastatic lymph node) and those at high risk (i.e., extended surgery, tumor localized in antrum, pT3-pT4, and 1 metastatic node).

From a practical point of view, the volume of resection should include the perigastric lymph nodes, those along the great vessels, those along the first centimeters of the splenic artery, but optionally those at the splenic hilum and at the hepatic pedicle. Should a complete dissection of the lymph nodes along the splenic artery be performed, it has been recently demonstrated in a randomized clinical trial that the same radicality and survival can be achieved preserving the tail of the pancreas.41With such a dissection we have been able to achieve a 5-year survival15 that is close (Fig. 6) to the gold standard (-71 %-75%)of the Japanese surgeon^.^' Finally, we should consider several points with regard to the tumors of the proximal stomach with or without invasion of the esophagus: Dissection of lymph nodes in the hepatoduodenal ligament (and the gnnc+ars to be a usemediastinal ones for esophagus-i1~va2i;1glesisns) "rr----less procedure, since there is no chance of long-term cure if they are m e t a s t a t i ~ . ~ Usually, ~ , ' ~ ~ , mediastinal ~~~ lymph nodes are not metastatic if , ~ ~ they ~ , are ~ ~ ~ the esophagus is involved only for 2 to 3 ~ m , 8 ~whereas involved in 15% to 19% of cases when there is transmural esophageal - infiltration." there is a fairly high involveAccording to several authors,61~79~90~95~132 ment of paraaortic nodes (15%to 33%of cases) except in pT1 patients.

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Months Figure 6. The survival of 600 patients undergoing an over D l subtotal or total RO gastrectomy for cancer.

The most detailed data regarding lymph node involvement in subcardial tumors are probably those from De Manzoni et alZ7who reported that paraaortic nodes were involved in 17%/20%/25% in pT2/pT3/pT4 patients undergoing a D4 lymphadenectomy, respectively. The splenic hilus was involved in 14% of pT3 tumors, and in 50% of pT4. The value of the dissection of paraaortic intercavaaortic and left lateroaortic lymph nodes is currently being investigated in Japan in a randomized clinical trial. CRITICAL ISSUES Splenectomy

It is well known that splenectomy increases early and late compli,~~,~~ cations and the length of postoperative stay. Few s t ~ d i e s ' ~ , 'h~ave looked at the effect of splenectomy on the oncologic outcome. TWO^^,^^ reported a statistically significant worse survival in patients undergoing splenectomy (but only at the univariate analysis), while Bozzetti et all5 found that splenectomy had a deleterious effect at the multivariate analysis as well. In conclusion, there is evidence that splenectomy should not be a standard procedure during gastrectomy, but should only be performed if there are adenopathies along the splenic vessels or in the splenic hilus that must be removed but cannot without splenectomy.

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Micrometastases Lymph nodes resected during gastrectomy are usually examined for metastases at light microscopy, although discrete carcinoma cells or their small aggregates are difficult to identify in the ordinary preparations stained with hematoxylin and eosin. Recent techniques of histochemistry or molecular biology, however, have enabled these occult metastases to be identified in paraffin sections: the so-called micrometastases. Such methodology usually consists of immunohistochemical staining with anticytokeratin antibody CAM 5.2 or against carcinoembryonic antigen or by amplification of cheratin 19 mRNA by reverse transcriptasepolymerase chain reaction or by using a CEA-specific nested reverse transcriptase-polymerase chain reaction. There is no consensus, however, regarding the definition of micrometastasis: some publications use upper limits of 0.2 to 2.0 mm while others use definitions based on the area of tumor involvement, such as less than 20% of the lymph node cross sectional area. The prevalence of micrometastases in lymph nodes previously defined pNO according to standard histopathologic examination varies 3.2%,l1711%,49 15%189 greatly in the literature, ranging from 1.5%,112%,21-22 to 17.6%.55In reference to the number of node-negative subjects, the percentage of patients who were finally converted to N+ stage ranged from 15%,55 30%,1139%,21-22 to 90%.l17 According to Mueller et al,85 18%of patients with 11-111 type adenocarcinoma of the esophagogastric junction had tumor cell microinvolvement in lymph nodes previously defined N-. It is still not known whether these cancer cells will proliferate or be removed by the host's immune response, or whether the patient could benefit from their dissection. The literature presents conflicting results, in part because of a discrepancy among the definitions of micrometastasis. Gunv6n et a146and Bozzetti et all1 did not find the presence of micrometastases to be prognostically ominous, while Siewert et allT7found that presence of three or more lymph nodes with micrometastases was of significant prognostic value in the pNO cases. Ishida et alS5reported a worse prognosis in patients with micrometastases in Stage I1 (not in Stage 111) and no statistically significant relationship between the number of occult-positive lymph nodes and survival. In patients with adenocarcinoma of the esophagogastricjunction Types I1 and 111, the survival of patients with micrometastases was similar to that of patients found to be pN+ using routine methods.85With regard to EGC, Maehara et all6 and Cai et aIZ1reported that the presence of . . iTiicromeIasIases in IjhT& i;il;dcsis 3550ciated with 2 poor psognosis,but this was not demonstrated at the multivariate The finding of Baba et a16 that a D2/D3 gastrectomy is associated with better long-term survival than a Dl gastrectomy in patients without lymph nodes metastases is noteworthy. These researchers speculated that one possible explanation could be an undetected minimal cancerous lymphatic invasion that is successfully amenable to a surgical dissection.

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SUMMARY

In this article it was not my intention to discuss therapeutic strategies for gastric cancer but more simply the principles underlying a surgical approach with a curative intent, when this appears to be feasible. As our diagnostic capacity for defining the stage of the disease prior to surgical exploration improves, a multidisciplinary approachespecially in pT3-pT4 tumors or in patients with positive peritoneal cytology-will become increasingly common. Preoperative chemotherapy, intraoperative radiation therapy, and intraoperative hyperthermic peritoneal chemoperfusion are already part of the oncologic armamentarium against advanced gastric cancer. It is likely that when patients are enrolled in these experimental protocols of combined treatments, the guidelines that I have reported here, which are primarily based on the concept that only RO surgery has a potential to cure patients, will change or be partially eroded, thanks to the contribution of the cytocide potential of the new therapies. References 1. Adachi Y, Ogawa Y, Sasaki Y, et al: Surgical results in patients with gastric carcinoma involving the mesocolon. Am J Surg 163:437439,1992 2. Adachi Y, Oshiro T, Okuyama T, et al: A simple classification of lymph node level in gastric carcinoma. Am J Surg 169:382-385,1995 3. Adachi Y, Shirasihi N, Shiromizu A, et al: Laparoscopy-assisted Billroth I gastrectomy compared with conventional open gastrectomy. Arch Surg 135(7):806-810,2000 4. Arima N, Adachi K, Katsube T, et al: Predictive factors for metachronous recurrence of early gastric cancer after endoscopic treatment. J Clin Gastroenterol29:4447, 1999 5. Asao T, Hosouchi Y, Nakabayashi T, et al: Laparoscopically assisted total or distal gastrectomy with lymph node dissection for early gastric cancer. Br J Surg 88:128-132, 2001 6. Baba H, Maheara Y, Takeuchi H, et al: Effect of lymph node dissection on the prognosis in patients with node-negative early gastric cancer. Surgery 117:165-169,1994 7. Bollschweiler E, Boettcher K, Hoelscher AH, et al: Preoperative assessment of lymph node metastases in patients with gastric cancer: Evaluation of the Mamyama computer program. Br J Surg 79:156-160,1992 8. Bonenkamp JJ, Hermans J, Sasako M, et al: Extended lymph-node dissection for gastric cancer. N Engl J Med 340:908-956,1999 9. Bonenkamp JJ, Songun I, Hermans J, et al: Randomized comparison of morbidity after D l and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 345:745-748,1995 10. Bozzetti F: Rationale for extended lymphadenectomy in gastrectomy for carcinoma. J Am Coll Surgeons 180:505-508,1995 11. Bozzetti F, Andreola S, Sirizzotti G: Prognostic effects of lymph node micrometastases in patients undergoing curative gastrectomy for cancer. Tumori 86(6):408411,2000 12. Bozzetti F, Bonfanti G, Bufalino R, et al: Adequacy of margins of resection in gastrectomy for cancer. Ann Surg 196:685-690,1982 13. Bozzetti F, Bonfanti G, Mariani L, et al: Early gastric cancer: Unrecognized indicator of multiple malignancies. World J Surg 24:583-587,2000 14. Bozzetti F, Bonfanti G, Regalia E, et al: How long is a 6-cm margin of resection in the stomach? Eur J Surg Onc 18:481483,1992 15. Bozzetti F, Marubini E, Bonfanti G, et al: Subtotal versus total gastrectomy for gastric cancer: Five-year survival in a multicenter randomized Italian trial. Ann Surg 230(2):170-178,1999

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