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Ann Surg. Jul 2000; 232(1): 81–89.
PMCID: PMC1421111

Functional Lymphatic Anatomy for Sentinel Node Biopsy in Breast Cancer

Echoes from the Past and the Periareolar Blue Method
Paul J. Borgstein, MD, PhD,* Sybren Meijer, MD, PhD,* Rik J. Pijpers, MD, PhD, and Paul J. van Diest, MD, PhD

Abstract

Objective

To simplify and improve the technique of axillary sentinel node biopsy, based on a concept of functional lymphatic anatomy of the breast.

Summary Background Data

Because of their common origin, the mammary gland and its skin envelope share the same lymph drainage pathways. The breast is essentially a single unit and has a specialized lymphatic system with preferential drainage, through select channels, to designated (sentinel) lymph nodes in the lower axilla.

Methods

These hypotheses were studied by comparing axillary lymph node targeting after intraparenchymal peritumoral radiocolloid (detected by a gamma probe) with the visible staining after an intradermal blue dye injection, either over the primary tumor site (90 procedures) or in the periareolar area (130 procedures). The radioactive content, blue coloring, and histopathology of the individual lymph nodes harvested during each procedure were analyzed.

Results

Radiolabeled axillary nodes were identified in 210 procedures, and these were colored blue in 200 cases (94%). The targeting concordance between peritumoral radiocolloid and intradermal blue dye was unrelated to the breast tumor location or the site of dye injection. Radioactive sentinel nodes were not stained blue in 10 procedures (5%), but this mismatching could be explained by technical problems in all cases. In two cases (1%), the (pathologic) sentinel node was blue but had no detectable radiocolloid uptake.

Conclusions

The lessons learned from this study provide a functional concept of the breast lymphatic system and its role in metastasis. Anatomical and clinical investigations from the past strongly support these views, as do recent sentinel node studies. Periareolar blue dye injection appears ideally suited to identify the principal (axillary) metastasis route in early breast cancer. Awareness of the targeting mechanism and inherent technical restrictions remain crucial to the ultimate success of sentinel node biopsy and may prevent disaster.

Sentinel node (SN) biopsy was first described 40 years ago by Ernest Gould et al. 1 In a remarkable manuscript, they proposed that “routine excision of the sentinel node be done for frozen section, as a method of deciding the necessity for doing a radical neck dissection in continuity with total parotidectomy for cancer of the parotid.” Since its revival in the early nineties, several groups of investigators have continued to demonstrate the validity and feasibility of SN biopsy in patients with breast cancer. 2–7 The uniformly high predictive values attained in these early studies can leave little doubt concerning the credibility of the SN concept.

The ultimate goal of performing SN biopsy in breast cancer is to avoid unnecessary axillary lymph node dissection (ALND), traditionally incorporated as a routine staging procedure. An important additional value of SN biopsy is that nodal staging is improved by almost 10% through focused pathologic examination of a few select lymph nodes. However, perhaps the most profound consequence of the SN concept is a better understanding of the intricate process of early lymphatic tumor dissemination and, in particular, of the kinetics and pathways involved in the metastatic spread of cancer.

Despite the encouraging preliminary results of SN biopsy reported by all investigators, words of caution may well be justified. 8,9 The procedure has been referred to as technically challenging and success rates vary considerably, according to the surgeon’s expertise (and dedication), various patient and tumor characteristics, and the identification method used. 4,9 False-negative rates differ significantly and the number of failures approach unacceptable levels in some initial studies, reporting sensitivities of less than 85%. 10,11 False-negative SNs are essentially the result of technical failures, many of which may be avoidable. There is clearly a need to improve the accuracy and efficacy of the technique before SN biopsy can be safely introduced into general surgical practice as the standard of care for breast cancer.

Successful SN biopsy depends primarily and unconditionally on accurate identification of the exact “metastatic route” that will be, or has been, used by disseminating tumor cells. Knowledge of the anatomy of the lymphatics is therefore of fundamental importance—not only knowledge of the topographic structure, but especially a concept of the functional, physiologic system as a whole. Such knowledge can be gained only through detailed observations during in vivo studies.

Based on our interpretations of the structural and functional anatomy of the lymphatic system of the breast, we formulated the following hypotheses:

  • • The lymph drainage of the skin directly overlying the breast is continuous with that of the underlying mammary gland proper and will drain to the same axillary sentinel lymph nodes.
  • • The breast functions as a single biologic unit and has a specialized lymphatic system that drains preferentially to designated (sentinel) lymph nodes in the lower axilla.

The purpose of this study was to test these hypotheses by comparing SN targeting using peritumoral radiocolloid with axillary lymph node staining after intradermal blue dye injection. On the basis of previous experience, 2 the lymph drainage pattern identified by intraparenchymal radiocolloid was considered to be the gold standard against which the lymphatic route visualized by intradermal blue dye was tested. Blue dye was initially injected into the skin overlying the breast tumor site. (The results of a pilot study have been reported elsewhere. 12) Later, the dye injection was consistently placed adjacent to the lateral border of the areola.

METHODS

Patient Selection

All patients with clinical stage T1–2, N0 breast cancer were eligible to take part in the prospective clinical trial after informed consent was obtained. Patients with palpable axillary nodes, large tumors (>5 cm), multifocal disease, prior radiation therapy, or extensive surgery to the breast or axilla, and pregnant women were excluded. The initial study design required SN biopsy to be complemented by full (level I–III) axillary dissection, but this procedure was adapted during the course of the study. Subject to patient consent, SN biopsy has become standard protocol in our hospital since November 1997, and ALND is now performed selectively if SN biopsy fails, if there is metastasis demonstrated, or if there are doubts concerning its reliability. The study was approved by the local ethics committee.

Preoperative Lymphoscintigraphy

All patients received peritumoral injections of radiolabeled tracer on the day before surgery. 2 A dose of 40 to 60 MBq 99m-technetium-labeled colloidal albumin (Nanocoll; Sorin Biomedica, Saluggia, Italy) in 4 mL saline was injected in two to four depots surrounding the primary tumor guided by palpation, or adjacent to the biopsy scar. Stereotactic- or ultrasound-guided injection was used in nonpalpable breast lesions. Scintigraphic images were obtained both 2 and 18 hours after injection, in anterior (with medial breast displacement) and lateral projections. The localization and number of all visible focal accumulations of radioactivity were recorded and labeled, according to their intensity, as primary hot spots (i.e., SNs) or as second-echelon “spill” foci.

Surgical Technique

After induction of general anesthesia and directly after sterile draping of the patient, 0.5 to 1 mL Patent Blue V dye (2.5% solution; Laboratoire Guerbet, Aulnay-sous-Bois, France) was injected strictly intradermally using a 27-gauge needle. In the initial set of patients, the single blue dye injection was placed into the skin directly overlying the corresponding primary tumor site (group 1). In a consecutive group of patients, the site of intracutaneous injection was consistently placed along the lateral border of the areola, irrespective of the breast tumor location (group 2).

After approximately 5 minutes’ delay, during which time the injection site was gently massaged, a 3- to 5-cm axillary incision was made in the standard location for ALND or the predetermined line for mastectomy. Careful dissection was performed under directional guidance of audio signals from the gamma detection probe (C-track; Care Wise, Morgan Hill, CA). Whenever possible, all blue lymphatic ducts encountered were pursued to the first draining lymph node or nodes (Fig. 1).

figure 12FF1
Figure 1. Two blue (axillary) lymphatic trunks clearly visible after periareolar intradermal blue dye injection. The vessels pass over the breast tissue and join to drain into a single blue sentinel node (held in the forceps) in the lower axilla.

In order of their discovery, all blue nodes were removed and the ex vivo radioactive count rate of each one was recorded separately. Lymph nodes with the most tracer uptake were defined as true SNs, whereas those with less than 50% of the highest count rate were considered to be secondary nodes. The complete retrieval of all radiolabeled lymph nodes, identified as primary hot spots on scintigraphy, was verified using the gamma probe. Only secondary foci with more than 10% of the uptake measured in the SN were also harvested.

Pathologic Examination

For standard histopathologic (hematoxylin and eosin) examination, lymph nodes less than 0.5 cm were completely embedded, those 0.5 to 1 cm were halved, and those more than 1 cm were cut in ±0.5-cm slices. All blue and/or radioactive specimens were subjected to additional (five-level) skip sectioning and immunohistochemical staining using CAM 5.2 (Becton-Dickinson, San José, CA). With the introduction of SN biopsy as standard protocol, intraoperative frozen-section analysis of the SNs was required; this procedure is described elsewhere. 13 Comprehensive documentation was kept of the individual radioactive content, blue coloring, anatomical location, and detailed histopathology of every sentinel and nonsentinel lymph node biopsied during each SN procedure.

RESULTS

Patient and Tumor Characteristics

From September 1996 to April 1999, 217 consecutive patients were enrolled in the study, including 1 man (Table 1). The age range was 31 to 87 years (mean 57 ± 12). Three patients had synchronous bilateral breast tumors, accounting for a total of 220 attempted SN procedures. Prior excision biopsy had been performed in 47 cases (21%), and 37 lesions (17%) were nonpalpable. Definitive breast surgery entailed mastectomy in 23% and lumpectomy in 77%. Tumor location followed the usual distribution among the different breast quadrants in both groups of patients (Fig. 2).

figure 12FF2
Figure 2. Tumor location in 220 procedures: distribution among the different breast quadrants. (UOQ, upper outer quadrant; LOQ, lower outer quadrant; C, central; UIQ, upper inner quadrant; LIQ, lower inner quadrant.)
Table thumbnail
Table 1. PATIENT DEMOGRAPHICS AND PRIMARY TUMOR CHARACTERISTICS

The tumor was eventually diagnosed as benign in four cases and as pure in situ carcinoma in another eight. Of the 208 invasive malignancies, 80% were classified as ductal carcinoma. Mean tumor size measured in the fresh pathology specimen was 1.9 ± 1.0 cm for the entire group, ranging from microinvasive (<1 mm) to more than 5 cm. Axillary lymph node metastases were ultimately detected in 86 of 216 (40%) malignant tumors.

Despite the initial study requirements, 22 of the first 80 SN procedures were not followed by ALND. This practice was specifically requested by 14 patients for personal reasons, whereas 8 patients had compromising medical factors favoring a conservative approach. Since the introduction of the current protocol, all 140 eligible patients chose to undergo SN biopsy with selective lymphadenectomy. ALND was thus performed in a total of 114 patients (52%), with an average of 14 ± 5 lymph nodes dissected (range 7–34).

Lymphoscintigraphy

Clear focal accumulations of radioactivity were visible in the ipsilateral axilla in 203 of 220 procedures (92%), with a mean of 1.2 ± 0.5. A single hot spot was seen in 165 axillae (81%), two equally intense foci in 34 (17%), and three in 4 (2%). Tracer spill to secondary nodes appeared in 79 cases (40%) but was limited to one second-echelon focus in 57 (72%). Scintigraphy failed to reveal obvious axillary nodal uptake in 12 (8%) procedures.

Parasternal lymph drainage to internal mammary nodes was visualized in 33 breasts (15%) occurring from all quadrants, although it was most common in upper inner lesions (26%) and least common in upper outer tumors (10%). Only three of these patients had no axillary transport. In one other patient, the only visible hot spot appeared to be infraclavicular.

Gamma Probe Detection

Radiolabeled axillary lymph nodes could be detected in 210 of 220 procedures (95%). A total of 247 individual SNs were harvested (average 1.2 ± 0.5 per axilla; range 1–3). A single SN was harvested in 180 patients (86%), two were harvested in 25 (12%), and three were harvested in 5 (2%). Median ex vivo nodal uptake was 385 counts/10 sec (range 32–>8,000). During 77 procedures (37%), a total of 98 secondary nodes were also radiodetected (range 1–3 nodes, mean 1.3 ± 0.5).

Despite negative results on lymphoscintigraphy, radiolabeled axillary nodes were discovered in 10 procedures. The SN had simply been obscured by radioactive scatter from the injection site in four patients. In six patients, including the three with only parasternal transport, the axillary SN exhibited minimal tracer uptake (<60 counts/10 sec).

Intradermal Blue Dye

The two groups were comparable with regard to patient demographics and tumor characteristics, including distribution among different breast quadrants (Tables 1 and 2). The degree of SN targeting visible on lymphoscintigraphy and the number of sentinel and secondary lymph nodes excised per axilla were also similar. Overall, SNs were successfully localized in 212 of 220 procedures (96%) and were clearly stained blue in 202 (91%). In 10 procedures (5%), SNs were detected by the gamma probe alone. All radioactive and/or blue SNs were located in the lower axilla (level I). The dye caused no adverse side effects, although a slight skin discoloration persisted for several months in some patients.

In group 1 (n = 90), blue dye was injected into the skin directly over the primary breast tumor. The exact site for intradermal injection was determined by the biopsy scar in 13 cases, by ultrasound or wire localization of 14 nonpalpable tumors, and by palpation in 63 procedures. SN biopsy failed in four cases, mainly because of lack of experience. SNs and/or their afferent lymph vessels were clearly stained blue in 81 of the 86 successful procedures (94%); in one case the blue SN did not contain radioactive tracer (Fig. 3). These blue SNs were found to harbor metastases in 35 cases; in 17 (including the nonradioactive SN), they were the only positive axillary nodes (Table 3). Blue SNs were free of tumor in 46 procedures. ALND was performed in 19 patients, and all axillary nodes were negative. Radiolabeled SNs were not blue in five cases (6%); in four early procedures, the time delay until SN retrieval was too long. In the fifth patient, a single unstained radioactive (false-negative) SN was removed at surgery, but several nodes in the ALND specimen were found to be blue.

figure 12FF3
Figure 3. Concordance between sentinel node uptake of peritumoral radiocolloid and intradermal blue dye: (A) in group 1, blue dye was injected at the tumor site (90 procedures); (B) in group 2, blue dye was injected in the periareolar area (130 procedures). ...
Table thumbnail
Table 3. SENTINEL NODE BIOPSY RESULTS IN GROUP 1 COMPARED WITH AXILLARY LYMPH NODE DISSECTION

In group 2 (n = 130), intradermal blue dye was injected along the lateral areolar border. SN biopsy failed in four patients (3%); three had previously undergone excision biopsy and one was found to have extensive nodal involvement. Axillary SNs were blue in 121 of 126 successful procedures (96%; see Fig. 3). In one patient a grossly involved SN had no detectable radiocolloid and was identified only by pursuing its blue afferent lymph vessel. Blue SNs were the only metastatic nodes in 26 of 41 positive cases (Table 4). Blue, radiolabeled SNs were negative in 80 cases. However, during one biopsy procedure, an obviously pathologic (nonradioactive, unstained) node was found preceding the false-negative SN. In another case, a blue (nonradioactive) enlarged positive node had been removed together with the negative SN. Radiolabeled SNs were not visibly blue in five patients (4%). Axillary exploration was attempted too soon after injection in two patients, and SN retrieval took relatively long in one. The fourth patient had a large excision scar over the upper outer breast quadrant; the unstained SN harvested was found to be falsely negative. In the fifth patient, a macroscopically involved blue secondary node preceded the unstained radiolabeled SN.

Table thumbnail
Table 4. SENTINEL NODE BIOPSY RESULTS IN GROUP 2 COMPARED WITH AXILLARY LYMPH NODE DISSECTION

Pathology

In 81 of 208 procedures (39%), SNs were found to harbor metastases (excluding the four benign primary lesions). There was one positive SN in 74 procedures, two in 6 procedures, and three in 1 procedure. Secondary node biopsies were also positive in 14 cases. SNs were the only involved axillary nodes in 46 procedures (57%); in 23 of these, micrometastases were detected by serial sectioning and immunohistochemical staining. Additional metastases were detected by completion lymphadenectomy in 29 patients (36%), ranging from 1 to 9 positive nodes. The remaining five patients (6%) with a positive SN refused subsequent ALND.

True SNs (defined on the basis of ex vivo radiocolloid content) were determined to be free from metastatic disease in 127 of 208 procedures (61%). However, as described above, other positive lymph nodes had been harvested during three biopsy procedures. Finally, unsuspected axillary metastases were revealed in one ALND. Although this was the only SN procedure (SN ± secondary/extra node biopsy) that failed to detect metastases, there were in fact four false-negative true SNs (i.e., most radioactive nodes).

DISCUSSION

Targeting Concordance

Our results demonstrate a remarkable concordance between SN targeting using peritumoral radiocolloid and intradermal blue dye. Identical axillary SNs were localized simultaneously by the two agents in 200 of 212 (94%) successful procedures. Almost without exception, these SNs were situated in the same relative anatomical position in the lower axilla. In most cases, one or two large blue lymph channels were seen to enter the axilla from the tail of the breast (see Fig. 1). The first lymph nodes found attached to these blue vessels practically always contained the greatest amount of radiocolloid uptake (i.e., the SN). This situation was encountered in both groups of patients and did not depend on the site of injection of either the peritumoral radiocolloid or the intradermal blue dye. The only exceptions occurred when these primary draining nodes had been grossly replaced by tumor.

Mismatch between radiocolloid labeling and blue coloring occurred in 12 patients; in 10 (5%) the radioactive SN was not stained blue. Most of these cases could be explained by “teething troubles” encountered during the learning phase of the study. Delicate surgical technique and correct timing are critical factors for successful blue dye mapping. Prior breast surgery may alter the original lymph drainage and lead to detection failure 2 or even false-negative SNs. 14 The opposite mismatching was rare: in only 2 of 212 procedures (1%) was a blue SN without radiocolloid uptake found. However, in no patients were other axillary nodes colored blue if the radiolabeled SN was not stained. Intradermal blue dye did not lead to excessive harvesting of colorful axillary lymph nodes.

Targeting Mechanisms

Detailed analysis of the metastasis detection rate of radiocolloid versus blue dye suggests that the dye may be more sensitive, particularly in extensive (sentinel) lymph node metastasis. In 10 of 86 node-positive cases (12%), the correct primary draining lymph node was identified by the blue dye and might have remained undetected if only a gamma probe had been used. In four procedures heavily involved, blue SNs exhibited very little radiocolloid uptake and localization was successful only because of their blue coloring. In five other cases, blue secondary nodes contained much larger tumor volumes than the more radioactive “true SNs” (four of which had micrometastases and one was falsely negative). Finally, in the patient with a false-negative unstained SN, several blue nodes were found among the multiple ALND metastases.

These observations reflect fundamental differences in the targeting mechanism of the two agents. Radiocolloid particles must be actively phagocytosed, retained, and accumulated in the lymph node. Consequently, adequate (residual) functional capacity of the SN is required to achieve detectable levels of radioactivity. 2 The small Patent Blue V crystals passively rely on prevailing fluid dynamics to produce an optically visible flow of lymph. 15

However, there comes a point when obstruction of flow by tumor leads to lymph rerouting through collateral vessels, thereby preventing any agent from reaching the correct (original) SN, as occurred in two of our patients. Awareness of this pitfall may help to prevent disaster but, ironically, this eventuality will always remain the most feared cause of a false-negative SN biopsy. 2

Functional Lymphatic Anatomy

The results from group 1 support the hypothesis that the skin envelope and the underlying glandular tissue of the breast share a common lymphatic pathway to the same draining axillary (i.e., sentinel) lymph nodes. 12 An independent group of investigators who adopted our technique of combining intradermal blue dye and intraparenchymal radiocolloid have confirmed these findings. 16

The mammary gland is embryologically derived from the ectoderm and eventually develops entirely within the superficial fascia of the skin. 17 The circumareolar lymphatic plexus on the external surface of the gland anastomoses with the superficial cutaneous lymph network of the overlying skin. 18 This specific relation was studied by Oelsner, 19 who described how the cutaneous lymphatics connect to the same axillary nodes as the mammary gland. It was confirmed by Rouvière, 20 who noted that the skin and breast lymph channels often joined together en route.

Undoubtedly, the most significant observation in our study comes from group 2. Periareolar blue dye identified the same lymphatic metastasis route as the peritumoral radiocolloid, regardless of the precise location of the tumor in the breast. Two reports 21,22 have suggested similar conclusions, and a recent study 23 appears to confirm this concordance. The breast functions as a single biologic unit, and the preferential lymph drainage pathway from all quadrants is essentially toward the same axillary (sentinel) lymph nodes. These observations are not as inconceivable or mysterious as they may appear to be.

Parenchymal lymph vessels accompany the lactiferous ducts centripetally to empty into the dense subareolar plexus of Sappey, where pooling of lymph from all parts of the breast occurs. 18 Generally, two enormous lymph trunks (vasa lymphatica mammaria magna 24) leave the areolar region to course superficially toward the lower axillary lymph nodes. Contrary to the widely accepted opinions of Turner-Warwick 25 and Haagensen, 26 the subareolar plexus does hold a key position in conveying lymph produced by the whole mammary gland toward the first lymph node filter of the axilla.

This unique arrangement of the breast lymphatic system, originally described by Sappey 27 and Sorgius 28 and later affirmed by many anatomists, 18–20,24,29–39 provides an adequate transport system capable of accommodating the dramatic surges of lymph flow occurring during lactation to preserve the physiologic balance. Logically, this will also be the preferential initial route for disseminating cancer cells, originating from any site in the breast, because these tumor emboli are passively carried along the direction of the prevailing lymph flow.

Direct dye injection 29,30 and indirect lymphoscintigraphy 2,31 studies have repeatedly shown that the breast cannot be divided into functionally separate segments. This explains why previous excision biopsy may merely reduce the detection rate, but will not necessarily affect the accuracy of SN biopsy—that is, unless prior (upper outer quadrant) excision has severed both main lymph trunks and the targeting agent is rerouted to an alternative “SN.”

Naturally, one cannot ignore the existence of alternative drainage pathways, but their significance in the initial spread of breast cancer is clearly overshadowed by the principal axillary route. The most important of all the accessory routes is the internal mammary pathway, and this was observed on lymphoscintigraphy in 15% of our procedures. However, only three procedures did not also reveal obvious axillary transport. Further, two of these patients had axillary node metastases identified by intradermal blue dye, but the parasternal “SNs” that underwent biopsy were free of tumor. Indeed, it is rare to find internal mammary node metastases in the absence of axillary involvement. 32

In the past, much emphasis has been placed on a variety of alternative lymphatic pathways, but these were mainly studied under nonphysiologic conditions (postmortem injections in putrefied cadavers) or were described in clinically advanced states of disease. These accessory pathways will, however, assume clinical importance once the main axillary drainage route has become obstructed.

It is of considerable importance that the correct (hot and blue) SNs were always found in the same relative anatomical location in the lower axilla. The only patient with an isolated level III hot spot had multiple axillary metastases, whereas the infraclavicular biopsy was negative. This preferential SN localization is confirmed by other studies, 4,6,7 and the sequential involvement of axillary nodes has also been clearly demonstrated in clinical studies. 33,34 Isolated skip metastases at upper levels are extremely uncommon in the absence of level I disease. 35 When only one node contains (occult micro-) metastasis, it is almost exclusively located in the lower axilla. 26,36,37

Several anatomical descriptions from the past have classified the complex axillary node barrier into separate, functionally defined lymph node groups. 26 In his classic work, Rouvière 20 explicitly related how the lymphatics of the anterior thoracic wall, including the mammary gland, essentially pass through the external mammary nodes (located along the lateral thoracic blood vessels of the axilla) and only rarely drain directly to nodes in the central or axillary vein groups. This group of primary draining lymph nodes of the breast, first described by Sorgius, 28 has been given various names by different anatomists: glandulae pectorales (Bartels 38), thoracales (Buschmakin 24), thoracales anteriores (Oelsner 19), or chaîne thoracique (Poirier and Cunéo 39). All these investigators had essentially reached the same conclusion: the passage of lymph from the mammary gland follows a systematic pattern through the seemingly disorganized mass of regional axillary nodes. In contemporary terms, the SN of the breast has a clearly defined position among a designated group of lower axillary nodes.

CONCLUSIONS

The lessons learned from this study provide a functional concept of the lymphatic system of the breast. The periareolar blue dye method appears to be perfectly suited to identify the single most important metastasis route. The only conceivable disadvantage is that it will not detect accessory pathways, but their clinical significance in early breast cancer is almost negligible compared with the predominant axillary route. The combination with peritumoral radiocolloid should overcome this problem, but the main objective of SN biopsy is currently to avoid unnecessary ALND.

Intradermal injection improves the efficacy of blue dye, because transport by skin lymphatics is more rapid and reliable than in the breast parenchyma. The blue dye can provide visual confirmation of removing the true first-draining lymph node by pursuing the efferent breast lymph trunks. Finally, because of its properties, blue dye may be inherently more sensitive than radiocolloid in certain patients. Combining the advantages of gamma probe detection with intradermal blue dye provides an accurate and efficient method of localizing the axillary SN in patients with breast cancer.

Footnotes

Correspondence: Paul J. Borgstein, MD, PhD, Dept. of Surgery, Onze Lieve Vrouwe Gasthuis, 1e Oosterparkstraat 279, 1091 HA Amsterdam, The Netherlands.

E-mail: pavlov@worldonline.nl

Accepted for publication December 27, 1999.

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