Clinical review: The implications of experimental and clinical studies of recruitment maneuvers in acute lung injury

Mechanical ventilation can cause and perpetuate lung injury if alveolar overdistension, cyclic collapse, and reopening of alveolar units occur. The use of low tidal volume and limited airway pressure has improved survival in patients with acute lung injury or acute respiratory distress syndrome. The use of recruitment maneuvers has been proposed as an adjunct to mechanical ventilation to re-expand collapsed lung tissue. Many investigators have studied the benefits of recruitment maneuvers in healthy anesthetized patients and in patients ventilated with low positive end-expiratory pressure. However, it is unclear whether recruitment maneuvers are useful when patients with acute lung injury or acute respiratory distress syndrome are ventilated with high positive end-expiratory pressure, and in the presence of lung fibrosis or a stiff chest wall. Moreover, it is unclear whether the use of high airway pressures during recruitment maneuvers can cause bacterial translocation. This article reviews the intrinsic mechanisms of mechanical stress, the controversy regarding clinical use of recruitment maneuvers, and the interactions between lung infection and application of high intrathoracic pressures.
Introduction
Mechanical ventilation (MV) is a supportive and life saving therapy in patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). Despite advances in critical care, mortality in these patients remains over 40% [1]. During the past decade the possibility that MV can produce morphologic and physiologic alterations in the lung has been recognized [2]. On histopathologic examination, findings in ventilator-induced lung injury (VILI) do not differ from those in ARDS [2]. To minimize this damage, lung protective strategies to avoid overdistension and cyclic collapse and reopening of alveoli have successfully been used in patients with ARDS receiving MV [3,4]. Recruitment maneuvers (RMs) consisting of sustained inflation to open the collapsed alveolar units have been proposed as an adjunct to MV in anesthesia and ARDS [5,6]. In most ARDS patients, however, lung recruitment and overdistension occur simultaneously at higher intrathoracic pressure [7]. Whether RMs can initiate cellular mechanisms of injury in healthy parts of the lung is unknown.
In the present review of the literature we describe the intrinsic mechanisms that explain how MV inflicts alveolar damage and the controversy regarding the use of RMs as an adjunct to MV. Finally, we discuss the interactions between lung infection and periodic application of high intrathoracic pressure, both in experimental models of ALI and in patients with ARDS.
Method
To identify the most relevant English language publications, the Medline database was searched using the following keywords: mechanotransduction, acute lung injury, acute respiratory distress syndrome, mechanical ventilation, ventilator-induced lung injury, overdistension, recruitment maneuvers, and bacterial translocation.
Many different methods of RM delivery have been proposed in the literature (Table 1). Several investigators have demonstrated that RMs can increase oxygenation and lung volume in collapsed prone lungs. However, the benefits of RMs in terms of oxygenation and lung recruitment in ARDS patients and in experimental models with alveolar flooding or consolidation are unclear.
Intrinsic mechanism of ventilator-induced lung injury
The mechanical stresses produced by MV at high pressure or volumes, and the forces generated by repeated opening and collapse lead to upregulation of an inflammatory response, with release of cytokines and chemokines and activation of neutrophils and macrophages that produce lung damage [2]. Injurious MV can lead to end-organ dysfunction, and the inflammatory cascade also plays a pivotal role in the systemic inflammatory response syndrome and in multiple organ system failure [8-10]. Like all adherent cells, alveolar epithelial cells interact with extracellular matrix through transmembrane adhesion receptors such as integrins. These receptors transmit forces from the surrounding matrix to the cytoskeleton via the focal adhesion complex [11]. When the basement membrane is strained, adherent epithelial cells must change shape and the ratio of their surface (plasma membrane) to their volume must increase. If the plasma membrane is disrupted the intracellular lipid stores are utilized to repair the cell surface. Most breaks are repaired within seconds, usually via a calcium-dependent response [12]. This dynamic remodeling process is the most important determinant of cell wounding [13].
Mechanotransduction is the conversion of mechanical stimuli, such as cell deformation, into biochemical and biomolecular alterations. How mechanical forces can be sensed by cells and converted into intracellular signals is still unclear, but in various experiments it was observed that mechanical stimuli activate the nuclear factor-κB – a critical transcription factor that is required for maximal expression of many cytokines involved in the pathogenesis of VILI [14]. It is unknown whether a single stimulus such as RMs applied during MV can trigger the above-mentioned pathways of lung injury, and the long-term benefits and safety of RMs will depend on the extent of this effect.
Experimental evidence on recruitment maneuvers
In saline lavaged rabbit lungs, Bond and coworkers [15] found an improvement in respiratory system compliance and oxygenation during high frequency oscillatory ventilation after RMs. In a similar model, Rimensberger and coworkers [16] showed that a single RM resulted in better oxygenation without augmenting histologic injury at positive end-expiratory pressure (PEEP) below the lower inflection point of the respiratory system pressure–volume curve, as compared with the group with PEEP set above the lower inflection point without RM. Furthermore, those investigators showed that a single sustained inflation to 30 cmH2O boosted the ventilatory cycle onto the deflation limb of the pressure–volume curve (Fig. 1). In other words, a RM applied in a recruitable lung increases the amount of recruited tissue at end expiration, favoring tidal ventilation.
Some data suggest that RMs have different effects depending on the type of lung insult and on the use of various combinations of tidal volume and PEEP. Whether RMs are necessary to prevent alveolar collapse when optimal PEEP is used remains controversial. Van der Kloot and colleagues [17] studied the effects of RMs on gas exchange and lung volumes in three experimental models of ALI: saline lavage, oleic acid, and pneumonia. After application of RMs, oxygenation improved only in the surfactant depletion group when low PEEP was used. At high PEEP in any model, RMs had no effect. Similar effects were observed in the study conducted by Bond and coworkers [15]. Takeuchi and colleagues [18] highlighted the difficulties in maintaining tidal ventilation at high lung volumes. Those investigators showed that, after RMs, PEEP set at 2 cmH2O above the lower inflection point was more effective in maintaining gas exchange and minimizing inflammation and lung injury than was PEEP set at the maximum curvature of the deflation pressure–volume curve. When recruitment is achieved with posture, Cakar and coworkers [19] showed better oxygenation after RMs in the prone than in the supine position, and importantly the benefit was sustained at lower PEEP. In other studies other adjuncts to MV were necessary to keep the lung open after RMs [20]. Lu and coworkers [21] demonstrated that RMs completely reversed the atelectasis, bronchoconstriction, and decrease in arterial oxygen saturation observed after endotracheal suctioning in an anesthetized sheep model.
In summary, the beneficial effects of RMs have been demonstrated in animal models of alveolar collapse induced by surfactant depletion. However, the pathobiology of ARDS is more complex and includes an altered vascular barrier function and alveolar flooding or consolidation. Indeed, in animal models other than that involving surfactant depletion, the effect of RMs on lung function is less evident.
Role of recruitment maneuvers in anesthetized patients
Formation of atelectasis and airway closure are mechanisms of impaired gas exchange in anesthetized patients with healthy lungs [22]. RMs have successfully been used to reverse collapsed dependent areas in these patients. Rothen and coworkers [22] found that a pressure of 40 cmH2O maintained for 7–8 s entirely re-expanded the collapsed lung tissue in anesthetized humans, although the net effect on gas exchange might be rather small if low ventilation/perfusion areas still coexist at the time of decrease in intrapulmonary shunt. Long-term effects of RMs in anesthetized patients depend on gas composition. Re-expanded lung tissue remained inflated for at least 40 min at low oxygen concentration [5], whereas lung collapse reappears within minutes with pure oxygen [23]. Finally, RMs followed by moderate PEEP may produce physiologic benefits in patients undergoing upper abdominal, thoracic, or laparoscopic surgery [24,25], and in patients prone to develop a moderate degree of lung injury after surgical procedures [26,27].
Recruitment maneuvers in patients with acute respiratory distress syndrome
Since the publication of the reports from Amato and coworkers [3] and the Consensus Conference on ARDS [28], the application of periodic RMs in patients with ARDS has gained acceptance among clinicians, although controversy remains. Among the earliest reports providing evidence that RMs improve lung function was that from Pelosi and coworkers [29], who demonstrated that sighs at 45 cmH2O plateau pressure in patients ventilated with PEEP at 14 ± 2.2 cmH2O significantly improved oxygenation, intrapulmonary shunt, and lung mechanics. Foti and colleagues [6] observed that RMs were effective in improving oxygenation and alveolar recruitment only during MV at low PEEP, suggesting that high PEEP better stabilized alveoli and prevented loss of lung volume. In the same line, Lapinsky and coworkers [30] reported beneficial effects on oxygenation, but this effect was sustained only if PEEP was increased after RMs. Lim and colleagues [31] found an improvement in oxygenation that persisted for 1 hour after an 'extended sigh'; this effect was partially lost soon after ventilatory support returned to the baseline PEEP level.
Other studies have shown a modest and variable effect of RMs on oxygenation when ARDS patients are ventilated with high PEEP. Richard and coworkers [32] demonstrated decreased oxygenation when tidal volume was switched from 10 to 6 ml/kg with PEEP set above the lower inflection point of the pressure–volume curve. However, increasing PEEP and RMs prevented alveolar derecruitment, and RMs performed in patients already ventilated with high PEEP had minimal effects on requirements for oxygenation support. Similarly, Villagrá and colleagues [33], studying the effect of RMs superimposed on a lung protective strategy (tidal volume <8 ml/kg and PEEP 3–4 cmH2O higher than the lower inflection point on the pressure–volume curve), found no effect on oxygenation regardless of the stage of ARDS, and in some patients venous admixture increased during RMs (Fig. 2). This deleterious effect suggested that the RMs increased lung volume by overdistending the more compliant already-opened and aerated alveolar units, favoring blood flow redistribution from overdistended to collapsed lung regions. Furthermore, a negative correlation was found between recruited lung volume induced by PEEP before RMs and RM-induced changes in oxygenation, suggesting that RMs are less effective when the lungs have been near optimally recruited by PEEP and tidal volume. Recently Hubmayr [34] suggested that alveolar flooding is probably the main mechanism of end-expiratory loss of lung aeration in human ARDS. This may explain, at least in part, why RMs are less beneficial in patients with ARDS. Nevertheless, when sudden lung derecruitment occurs in conditions of adequate PEEP ventilation, such as the loss in lung volume produced during secretion aspiration, Maggiore and coworkers [35] observed that suctioning-induced lung derecruitment can be prevented by performing RMs.
The cause of ARDS may also influence the response to RMs. In a majority of trauma patients developing ARDS, Johannigman and coworkers [36] found an improvement in oxygenation after RMs in patients receiving MV with low tidal volume and high PEEP. However, when Bein and colleagues [37] analyzed the impact of RMs on intracranial pressure and cerebral metabolism in patients with acute cerebral injury and respiratory failure, they observed an increase in intracranial pressure at the end of RMs and a subsequent reduction in mean arterial pressure resulting in a decrease in cerebral perfusion pressure. Both normalized 10 min after RMs. Grasso and coworkers [38] found that RMs significantly improved arterial oxygenation and lung volume in patients with early ARDS without impaired chest wall mechanics (i.e. with large recruitment potential). Nevertheless, in the group with low chest wall compliance, RM-induced lung overdistension reduced blood pressure and cardiac output, making RMs ineffective and potentially harmful (Fig. 3).
RMs can also be applied during assisted breathing in non-sedated patients. Patroniti and coworkers [39] applied one sigh per minute to baseline pressure support ventilation in patients with early ARDS. They observed a significant improvement in arterial oxygenation associated with an increase in end-expiratory lung volume and respiratory system compliance during the sigh, suggesting that sighs promote alveolar recruitment. These changes returned to baseline after the sighs were discontinued.
Other studies emphasize the importance of body posture (supine or prone) on regional distribution of intrapulmonary ventilation and perfusion, and the beneficial effects of prone position in limiting VILI in experimental animals [40]. Lim and coworkers [31] found that the benefit was significantly greater when patients were in the supine position as compared with those in the prone position, suggesting that patients in the prone position have less collapsed lung. These findings were recently confirmed by Pelosi and colleagues [41], who demonstrated that adding cyclical sighs during ventilation in the prone position provided optimal lung recruitment in the early stage of human ARDS.
Finally, two randomized physiologic pilot studies of RMs superimposed on low tidal volume ventilation and moderate to high PEEP conducted in approximately 100 patients with ALI showed no clear benefits in terms of oxygenation [42,43]. Moreover, RMs were potentially harmful because some patients developed hemodynamic instability, ventilator dysynchrony, and pneumothorax after RM.
In summary, RMs can be useful in improving oxygenation in patients receiving MV with low PEEP and low tidal volume. However, in patients with ARDS receiving MV with high PEEP levels, the beneficial effects of RMs disappear. RMs may restore lung volume and oxygenation in endotracheal suctioning-induced lung derecruitment in mechanically ventilated patients diagnosed with ALI/ARDS. RMs should be avoided in patients with suspected or documented intracranial hypertension, in patients with a stiff chest wall, and in patients in the late stage of ARDS.
Lung infection and mechanical ventilation
Recent studies suggest that the detrimental effect of MV may be aggravated when lungs are infected or primed with endotoxin. In ex vivo rat lungs, Ricard and coworkers [44] showed that ventilation that severely injures lungs does not lead to release of significant amounts of inflammatory cytokines by the lung in the absence of lipopolysaccharide challenge. Likewise, in experimental studies other investigators have shown that MV predisposes to development of pneumonia [45] and that coexisting MV and infection have a strong impact on the lung because they appear to act synergistically in causing alveolar damage [46]. Finally, when bacteria were injected in animals with previous severe ALI, MV produced a clinical picture closely resembling that of hyperdynamic sepsis in humans [47]. These experimental studies taken together suggest that in the presence of lung infection MV (cyclic positive intrathoracic pressure) predisposes to greater bacterial burden and bacterial translocation from the lung into the systemic circulation than would occur without MV. These effects are particularly important when using ventilatory strategies that apply large transpulmonary pressures (high tidal volume and/or high alveolar pressures without PEEP) [48] and are partially attenuated when protective ventilatory strategies are used [49].
RMs can be applied as sighs or as periodic sustained inflations that can damage or transiently alter the integrity of the alveolar–capillary barrier [50,51]. Whether such strategies to improve lung function can result in failure of the alveolar–capillary barrier and promote transient bacterial translocation in humans remains unknown. The amount of recruitable lung parenchyma in patients with ALI/ARDS receiving MV is a matter of debate, and controversy exists on the use of RMs in such patients for two main reasons. First, consolidation (non-recruitable lung parenchyma) and sticky atelectasis (potentially recruitable) coexist in different amounts in ALI/ARDS, and cannot be distinguished and quantified at the bedside to inform a decision regarding a recruitment strategy. Second, the amount of lung tissue to be recruited in some ARDS patients is sparse [52]. Therefore, RMs can exert little effect on consolidated lung areas but can cause overdistension in some lung regions where bacteria are compartmentalized at the site of infection or colonization. Because spillover of lung cytokines into the systemic circulation is observed in lung inflammation and is potentiated with MV [53], a similar phenomenon is likely to occur when the concentration of bacteria in the lungs is high enough. In a recent study [54] it was found that high pressure ventilation promoted early translocation of bacteria; however, intermittent RMs applied as a sustained inflation superimposed on low-pressure ventilation without PEEP did not cause translocation of intratracheally inoculated Pseudomonas aeruginosa in rats with previously healthy lungs. However, we do not yet know whether the lung injury model used is valid for human ARDS or the degree of reproducibility of short-term experimental studies in patients receiving MV for days or weeks [55].
Conclusion
On the basis of our review of the literature on experimental and clinical studies, considerable uncertainty remains regarding the use of RMs in humans with ARDS. RMs may have a role to play in patients with early ARDS and normal chest wall mechanics because there is great potential for alveolar recruitment, and after disconnections from the ventilator, when sudden loss of lung volume promotes alveolar instability and derecruitment. Recommendations to use RMs as adjuncts during lung protection ventilatory strategies seem unnecessary because sustained improvements in lung function have not been found when the strategies are combined. The presence of lung infection must be considered a major limitation for aggressive RMs because translocation of bacteria and the occurrence of systemic sepsis have been demonstrated in animal models. Finally, large randomized studies do not support the use of RMs in patients with ARDS.
In conclusion, the use of RMs cannot be recommended in the light of current knowledge, and if RMs are used they should be restricted to an individualized clinical decision or to a last resort to improve oxygenation and lung mechanics in a severely hypoxemic ARDS patient.
Competing interests
None declared.
Abbreviations
ALI = acute lung injury; ARDS = acute respiratory distress syndrome; MV = mechanical ventilation; PEEP = positive end-expiratory pressure; RM = recruitment maneuver; VILI = ventilator-induced lung injury.

acute lung injury
mechanical ventilation
mechanical stress
lung infection
lung collapse


In addition to conventional open surgery and endoscopic techniques, laparoscopic correction of vesicoureteric reflux, sometimes even robot-assisted, is becoming an alternative surgical treatment modality for this condition in a number of centres around the world. At least for a subgroup of patients laparoscopists are trying to develop new techniques in an effort to combine the best of both worlds: the minimal invasiveness of the STING and the same lasting effectiveness as in open surgery. The efficacy and potential advantages or disadvantages of these techniques are still under investigation. The different laparoscopic techniques and available data are presented.
Introduction
When confronted with the title “What is new in surgical treatment of vesicoureteric reflux?” many readers will automatically think of endoscopic techniques with subureteric injection of bulking agents, also known as STING (Subureteral Teflon INjection). Over the years several substances have been advocated as bulking agents, but the original Teflon is no longer in use. (The most commonly used substance nowadays is DefluxR, a dextranomer/hyaluronic acid copolymer.) However, a technique that has been around for a quarter of a century can hardly be considered for a text on surgical novelties. Instead, this review concentrates on the use of laparoscopic techniques in this setting.
General considerations about vesicoureteric reflux
Vesicoureteric reflux (VUR) remains one of the most frequent conditions in paediatric urology, although the exact prevalence is largely unknown. VUR can be primary, secondary (e.g. to elevated bladder pressures in neurogenic bladders or dysfunctional voiding) and sometimes intermittent in nature, only disclosing itself when infection has possibly induced a degree of insufficiency of the ureterovesical junction. It is generally assumed that VUR predisposes to urinary tract infections and that surgical treatment of reflux and prophylactic antibiotics are equivalent in terms of preventing infections and renal scarring. The relative merit of these interventions in the natural course of these conditions remains to some extent controversial [32].
The importance of voiding dysfunction with detrusor overactivity, underactivity or dysfunctional elimination disorder in the aetiology of VUR should not be underestimated [4, 30] and this has its implications in the treatment offered to these children. Hence bladder training and minimally invasive techniques have acquired a prominent role over the years. Children with VUR and concomitant voiding dysfunction are likely to suffer more breakthrough infections and have lower spontaneous resolution rates and therefore represent a large proportion of the patients undergoing surgical intervention [31].
Antimicrobials form the mainstay in the treatment of VUR, in combination with other conservative measures, because VUR will spontaneously disappear in a majority of children and rarely gives rise to serious long-term complications [2]. Increasingly however the exact role of prophylaxis is being questioned as well-designed prospective trials are rare [10]. Nevertheless, a small subgroup of patients does pose problems of break-through infections despite all conservative measures and in fact some of them seem prone to renal scarring leading to hypertension and exceptionally even end stage renal failure [16].
Traditional surgical techniques in the treatment of VUR
Since the 1950s several surgical techniques have been developed for the correction of VUR. All techniques share the same basic principle of creating an anti-reflux mechanism by increasing the portion of the distal ureter lying in a submucosal tunnel between the detrusor muscle and the bladder mucosa. They offer comparable and very high success rates with few complications [12]. From a purely technical standpoint, these open techniques can basically be divided into two groups. There are those that involve mainly or entirely intravesical ureteral dissection (and hence a need for postoperative bladder drainage) and those that use a purely extravesical approach to the ureter without disconnecting it from the bladder. To the former group belong the techniques of Politano and Leadbetter (1958), Glenn and Anderson (1967), the psoas-hitch technique and the (most widely used) Cohen technique (1975) [6, 11, 13, 25]. In these techniques the ureter is disconnected from the bladder and reimplanted in a new and longer submucosal tunnel from the luminal side of the bladder. In the Cohen technique, a cross-trigonal tunnel is created bringing the ureter to the contralateral side, the other techniques result in a more natural course of the ureter, but are somewhat more prone to complications such as bowel injury or kinking of the ureter. The psoas-hitch technique is generally reserved for more complex situations as in mega-ureters or re-do surgery and is helpful in creating a longer tunnel. The conceptually different extravesical approach was popularized by Lich and Gregoir, reducing postoperative bladder irritation to insignificance, but predisposing to temporary bladder retention when performed bilaterally [14, 21].
The more recent and certainly minimally invasive STING technique where bulking agents are injected submucosally has gained wide acceptance. Undoubtedly this is technically a very easy, relatively cheap and patient-friendly treatment modality, tempting many doctors into an increasingly pre-emptive approach to VUR, using it as first-line treatment in cases of (antenatally detected) high-grade reflux even in infants [27]. Success rates, even in low-grade reflux, are clearly lower than in open surgery and a second injection of bulking agent is often necessary [8]. Moreover, prospective randomised trials and long-term results are still not available. The tendency to use this endoscopic technique as an alternative to medical treatment is underscored by the fact that since the Food and Drug Administration (FDA) approval of DefluxR the total number of procedures for reflux has increased, while open surgery rates have remained stable [20].
All these facts and tendencies mentioned above in turn suggest that, at least for the foreseeable future, there will remain a group of patients in whom STING is deemed-or proves to be-insufficient. Open surgery on the other hand has its drawbacks as well due to its invasiveness. In an ideal world physicians would be able to define very precisely and at the earliest possible point in time which group of patients with VUR is at increased risk for the complication of pyelonephritic scarring and which group is not. This would in turn allow a very tailored approach to each individual child with pre-emptive surgical measures in the group at risk. Failing this knowledge, the next best thing to aim for is to combine the superior results of time-honoured open procedures like a Cohen reimplantation or Lich-Gregoir operation with the much sought after minimal invasiveness of laparoscopy, possibly with the added ultra-precise tissue handling and dexterity of robotic surgery. These considerations are the driving force of the developments described in this text.
Conventional laparoscopic techniques
Both intra- and extravesical laparoscopic treatments have been described in a great variety of techniques. Most series however remain small and follow-up is very limited. Ehrlich et al. and Janetschek et al. were the first to report in 1994 and 1995 on two and six children undergoing laparoscopic Lich-Gregoir anti-reflux surgery for vesicoureteral reflux [7, 17]. The reflux was successfully corrected without morbidity, requiring only a short hospitalisation. Peri-operative ureteral stents were deemed unnecessary. One mild unilateral stenosis did develop later, requiring temporary stenting. Ehrlich et al. described decreased peri- and post-operative pain and improved cosmesis by comparison with open surgery. He suggested that this preliminary report deserved further study. Janetschek et al. on the other hand concluded that the Lich-Gregoir anti-reflux procedure was a complicated one because of the difficult suturing and knot-tying, offering no clear advantage over the conventional procedure. Other teams were very reluctant to join in the efforts to develop this approach for several years to come. The choice for a Lich-Gregoir technique for the first attempts at correction of VUR can be explained by the fact that, at that time, experience with laparoscopy in cavities other than the abdomen was very limited. Five years later Lakshmanan and Fung reported technical modifications to further minimize invasiveness, basically by downsizing ports and instruments and limiting tissue dissection [19]. A more recent paper by Riquelme et al. again reported excellent outcomes in 15 children, even in cases of bilateral reflux and duplex ureters [28]. There was no postoperative voiding dysfunction. Laparoscopic ureteral reimplantation with extracorporeal tailoring and stenting of megaureters combined with a Lich-Gregoir type of extravesical reimplantation was recently reported by Ansari et al. in three children [1].
Although the Cohen procedure was the more widely used in the treatment of VUR, a laparoscopic version thereof was investigated later than the extravesical laparoscopic techniques. The obvious reason is the anticipated difficulties with port placement and the limitations of the intravesical working space. Different approaches were used by Gill et al. and Yeung et al. [12, 33]. Gill et al. combined the use of two suprapubic ports with a transurethral resectoscope for unilateral cases whereas Yeung et al. used three suprapubic ports, more closely copying the open Cohen procedure.
A recent report by Kutikov et al. on either transvesical laparoscopic cross-trigonal ureteral reimplantation in patients with reflux or a Glenn-Anderson reimplantation in patients with a primary obstructing mega-ureter mentions operative success in 25 of 27 patients with VUR and 4 out of 5 patients with mega-ureters, results that are comparable to the ones obtained in open surgery [18]. Complications were postoperative urinary leak in four patients and ureteral stricture at the anastomosis in two. The authors noted that most complications occurred in the younger patients with small bladder capacities.
For completeness two papers on reimplantations in (young) adults can be mentioned. Chung et al. described successful laparoscopic nonrefluxing ureteral reimplantation with a psoas hitch using a submucosal tunnelling technique after submucosal injection of saline under cystoscopy in two adult female patients without postoperative complications [5]. Also in 2006, Puntambekar et al. described laparoscopic extravesical ureteroneocystostomy with psoas hitch in five gynaecologic patients, clearly minimizing the procedural morbidity [26]. Again no intraoperative or postoperative complications occurred.
Gradually more relevant series with larger numbers of patients and longer follow-up are being presented. At the 2007 European Society for Paediatric Urology (ESPU) annual meeting two groups will present their experience in about 80 patients each, with success rates above 90% (http://www.espu.org).
Robot-assisted techniques
Over the last 2 years a few authors reported robot-assisted laparoscopic techniques using the Da VinciR (Intuitive Surgical, Mountain View, CA) system for the treatment of VUR, adding yet another approach to this rapidly expanding field [3, 23, 24]. They made good use of the experience gained with conventional laparoscopy, adding the advantages of robotics: enhanced dexterity of the instruments, absence of tremor and 3-D vision. The generally used term of “robotic surgery” is to some extent actually misleading because it suggests completely autonomous function of the equipment. In reality it works as a master-slave system, merely transferring the movements of the surgeon’s hands to the tip of the instruments (Fig. 1). The evolution parallels the one seen in conventional laparoscopy, experience having started with the extravesical approach and later moving to intravesical procedures. The sequence of surgical steps of both techniques will briefly be discussed. As stated, they closely mirror the steps in conventional laparoscopy.
Fig. 1Outside view once the draped robotic arms are connected to the laparoscopic ports: the child seems completely “embraced” by the machine
Extravesical technique
To start, a cystoscopic evaluation of the relevant anatomy is carried out. The camera port is then placed in the umbilicus and the two working ports in each lower abdominal quadrant. A small transverse peritoneal incision is made on the laterodorsal side of the bladder where the ureter is retrieved. The ureter is then buried in a trough between the mucosa and detrusor to create the anti-reflux mechanism (Figs. 2 and 3). The bladder catheter is removed already at the end of the procedure unless a significant perforation needing suturing of the mucosa has been made.
Fig. 2Extravesical approach: very gently the detrusor muscle is incised and peeled away until the delicate bladder mucosa starts to bulgeFig. 3Extravesical approach: the completely freed ureter is hinged into the trough to create an anti-reflux valve mechanism
In our experience there were no bladder symptoms post surgery in any of the patients. All cases of reflux resolved, but there was one case of “de novo” contralateral low-grade reflux [3]. Later we successfully performed this operation in an adult male patient after a failed subureteral injection (unpublished data). Interestingly, Elmore et al. recently reported on the use of the open Lich-Gregoir technique as salvage in these patients as well [9] and already in 2004 one similar laparoscopic patient was reported by Shu et al. [29]. Both in open and laparoscopic surgery this was a novel approach, meant to avoid the sometimes difficult intravesical dissection due to foreign material after STING. Peters and Borer reported persisting low-grade reflux in 2 of their 24 patients [23].
Intravesical technique
Olsen was the first to experiment with a Cohen cross-trigonal ureter reimplantation by laparoscopic access to the bladder in a pig model using the Da VinciR system [22]. In all pigs the reflux disappeared after the procedure. The advantage of the robotic equipment seemed to be the better access to submucosal tunnelling of the ureter and the intravesical suturing of the anastomosis. Peters and Woo in 2005 and Callewaert in 2006 reported their experience with robot-assisted Cohen procedures in six and three paediatric patients respectively [3, 24].
Initial port placement and closure of the incisions at the end of the procedure were the crucial steps, the rest of the procedure being straightforward. Once inside the bladder the mucosa is circumferentially incised around the ostium using the cautery hook. After both ureters are freed, a submucosal tunnel connecting the most proximal part of the two mucosal incisions is created, using forceps and scissors (Fig. 4). Creation of the submucosal tunnel and reimplantation of the ureters is remarkably easy because of the three dimensional visualisation and great dexterity inside the very small volume of a child’s bladder. The anatomical detail is such that dissection of the plane between the detrusor and mucosa is achieved with more detail than in open surgery. The bladder catheter is left indwelling for 24 to 48 h.
Fig. 4Intravesical approach: creation of the submucosal tunnel connecting the periureteral incisions. (The jaws of the forceps measure 5 mm in length)
We had one conversion to open surgery out of three cases in our early experience because of port-related problems in a small child [3]. Kutikov et al. using conventional laparoscopy similarly found that the smaller children were more prone to complications and that these procedures were technically more demanding [18]. Peters and Woo on the other hand reported no conversions in a series of six children aged between 5 and 15 [24]. They did however have a case of port-site urinary leakage requiring prolonged bladder drainage.
Peters and Callewaert each reported one case of persisting low-grade reflux in their initial experience. Unlike the situation in open surgery, bladder spasms remained completely absent and anticholinergics were unnecessary. This fact is highly suggestive of the minimal invasiveness and limited trauma incurred by the bladder wall.
When comparing the robotically assisted intra- and extravesical operations it is our impression that the Lich-Gregoir technique offers some advantages over the intravesical operation: no need for catheters, no haematuria and easier reproducibility. The drawback is that the abdominal cavity needs to be entered. The abdominal cavity even in smaller children is large enough to allow comfortable movement of the instruments, whereas intravesical operations in this patient group can be technically impossible due in part to the relative bulkiness of the robotic instruments.
Conclusion
Treatment modalities of reflux are evolving rapidly. Conventional or robot-assisted laparoscopic techniques must be considered a possible future alternative to the more traditional ways of treating this condition. There is no proven superiority at this time and experience is limited to a few centres only and relatively small numbers of patients. It is well established that with open surgery very high success rates can be achieved and that morbidity is relatively low and hospitalisation nowadays can be kept short. The first impressions are that morbidity using laparoscopic techniques is lower still and that there is some cosmetic gain, but it is obvious that the most important issue will be whether the long-term success rates are at least comparable.
Most surgeons agree that robotics certainly add to the precision and ease of the individual surgical steps when compared to conventional laparoscopy, but the financial costs are very high. The intravesical approach using robotics is feasible, but technical difficulties must be taken into account in smaller children. (The same holds true for the conventional laparoscopy.) The extravesical robotic approach clearly seems the more promising, possibly even after failed submucosal injection therapy. Nevertheless we feel that the intravesical approach deserves further pursuing because it may allow surgical correction of other malformations at the level of the bladder neck and ureterovesical junction in a minimally invasive and very precise way.
It would be premature to promote laparoscopy as the golden mean between STING and open surgery for a subgroup of reflux patients at this point, as this would imply diverting a large number of patients to a few centres where either the technical laparoscopic expertise or a robotic system is available. However, we remain convinced that in the (near) future laparoscopy will find its place in the care for these patients.


Population-Based Study of Islet Cell Carcinoma

Background We examine the epidemiology, natural history, and prognostic factors that affect the duration of survival for islet cell carcinoma by using population-based registries.
Islet cell carcinomas are low- to intermediate-grade neuroendocrine carcinomas of the pancreas. Also known as pancreatic endocrine tumors or pancreatic carcinoid, they account for the minority of pancreatic neoplasms and are generally more indolent than pancreatic adenocarcinoma. Islet cell carcinomas, which arise from islets of Langerhans, can produce insulin, glucagon, gastrin, and vasoactive intestinal peptide, causing the characteristic syndromes of insulinoma, glucagonoma, gastrinoma, and VIPoma. Pancreatic polypeptide is also frequently produced, yet it is not associated with a distinct clinically evident syndrome.
Although the molecular biology of sporadic islet cell carcinoma is less well understood than other more common solid tumors, they can arise in connection with several hereditary cancer syndromes. The best known of these, multiple endocrine neoplasia type 1 (MEN1), is an autosomal-dominant inherited disorder characterized by tumors of the parathyroids, pituitary, and pancreas.1 Less commonly, neuroendocrine (carcinoid) tumors of the duodenum (gastrinomas), lung, thymus, and stomach have also been described.2
Tuberous sclerosis and neurofibromatosis are two other hereditary cancer syndromes associated with the development of neuroendocrine tumors. TSC1/2 complex inhibits mTOR and is normally expressed in neuroendocrine cells.3 Patients with a defect in the TSC2 gene have tuberous sclerosis and are known to develop islet cell carcinoma.4 Neurofibromatosis is associated with the development of carcinoid tumors of the ampulla of Vater, duodenum, and mediastinum.5,6 The gene responsible for neurofibromatosis 1 (NF1) regulates the activity of TSC2. The loss of NF1 in neurofibromatosis leads to constitutive mTOR activation.7 Finally, islet cell carcinomas also occur in approximately 12% of patients with von Hippel-Lindau disease (vHL).8 The vHL gene is located on chromosome 3p26–p25; inactivation of the vHL gene is thought to stimulate angiogenesis by promoting increased HIF-1α activity.
Little is known about the epidemiology and natural history of islet cell carcinoma. Although several case series have been reported, there have been few population-based studies. This is in part due the uncommonness of this disease as well as the complexity of its classification. Although pancreatic carcinoid based on ICD-O-3 histology classification (8240–8245) has been partially described in studies of carcinoid from the Surveillance, Epidemiology, and End Results (SEER) Program,9 these have been incomplete analyses because most islet cell carcinomas were coded differently in the ICD-O-3 system (8150–8155). Survival of patients with islet cell tumors was also described in a recent report on malignant digestive endocrine tumors that was based on data from England and Wales.10 In this population-based study, we have undertaken a comprehensive analysis of patients with islet cell carcinoma identified through the SEER Program database in the United States.
METHODS
The SEER Program was created as a result of the National Cancer Act of 1971. The goal of the SEER Program is to collect data useful in the prevention, diagnosis, and treatment of cancer. In this study, we used the SEER data based on the November 2005 submission. For incidence and prevalence analyses, registry data was linked to total U.S. population data from 1969 to 2003.11
Since 1973, the SEER Program has expanded several times to improve representative sampling of minority groups as well as to increase the total sampling of cases to allow for greater precision. The original SEER 9 registries included Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco–Oakland, Seattle–Puget Sound, and Utah. In 1992, four additional registries were added to form the SEER 13 registries, which included the SEER 9 registries, plus Los Angeles, San Jose–Monterey, rural Georgia, and the Alaska Native Tumor Registry. More recently, in 2000, data from greater California, Kentucky, Louisiana, and New Jersey were added to the SEER 13 Program to form the SEER 17 registries. SEER 9, 13, and 17 registries cover approximately 9.5%, 13.8%, and 26.2% of the total U.S. population, respectively. The data set we use here contains information about a total of 4,539,680 tumors from 4,123,001 patients diagnosed from 1973 to 2003.
Islet cell carcinomas were identified by search for ICO-O-3 histology codes 8150–8155, 8240–8245, and pancreatic primary site (duodenal gastrinomas were excluded). The included histology codes correspond to the following clinical/histologic diagnoses: islet cell carcinoma, insulinoma, glucagonoma, gastrinoma, mixed islet cell/exocrine carcinoma, VIPoma, carcinoid, enterochromaffin cell carcinoid, and adenocarcinoid. The SEER registries include neuroendocrine neoplasms that are considered invasive and malignant (behavior code of 2 or 3 in the International Classification of Diseases for Oncology, 2nd edition [ICD-O-2]). Cases designated as poorly differentiated or anaplastic were excluded. A total of 1310 cases of islet cell carcinoma were included in this study. Cases identified at the time of autopsy or by death certificate only were excluded (36 cases) from survival analyses.
Although a tumor, node, metastasis system classification system has recently been proposed,12 during the period of time that we studied, there was no accepted staging system for islet cell carcinoma. Here, we use the SEER staging system. Tumors in the SEER registries were classified as localized, regional, or distant. In this system, a localized neoplasm was defined as an invasive malignant neoplasm confined entirely to the organ of origin. A regional neoplasm was defined as a neoplasm that has (1) extended beyond the limits of the organ of origin directly into surrounding organs or tissue; (2) involves regional lymph nodes; or (3) fulfills both of the above. A distant neoplasm was defined as a neoplasm that has spread to parts of the body remote from the primary tumor.
The comparisons between patients, tumor characteristics and disease extension were based on the χ2 test. One-way analysis of variance was used for the comparison of continuous variables between groups. Survival duration was measured by the Kaplan-Meier method and compared by the log rank test. The statistical independence between prognostic variables was evaluated by multivariate analysis by the Cox proportional hazard model.
SEER*Stat 6.2.4 (Surveillance Research Program, National Cancer Institute) was used for incidence and limited-duration prevalence analyses.13 All other statistical calculations were performed by SPSS 12.0 (Apache Software Foundation 2000). Survival durations calculated by SPSS were also verified by parallel analyses by SEER*Stat. Comparative differences were considered statistically significant when the P value was <.05.
RESULTS
Frequency and Incidence
Between 1973 and 2003, a total of 101,192 pancreatic neoplasms in 101,173 patients were identified in the SEER 17 registries. Among these, 101,046 neoplasms were classified as malignant and occurred in 101,029 patients. When we restricted the search to codes of neuroendocrine histology, a total of 1385 neoplasms in 1385 patients were identified. We removed 75 patients who were classified as having tumors of poorly differentiated or anaplastic grade. Thus, a total of 1310 patients had pancreatic islet cell carcinomas in the SEER registries. This consisted of 1.3% of all patients with pancreatic cancers.
By using linked population files, we calculated the incidence of islet cell carcinoma as a rate per 100,000 per year, age-adjusted to year 2000 U.S. standard population. Because the SEER 9, 13, and 17 registries were linked to different population data sets, we computed the age-adjusted incidence rates in three time periods. The age-adjusted incidence in the SEER 9 registries between 1973 and 1991 was .16 per 100,000. For the SEER 13 registries, from 1992 to 1999, an age-adjusted incidence of .14 per 100,000 was observed. Finally, for the period covered by the SEER 17 registries, from 2000 to 2003, the age-adjusted incidence rate was .12 per 100,000. This suggests that on the basis of the current U.S. population estimate of 302 million, approximately 362 cases of malignant islet cell carcinoma will be diagnosed each year. The number of small benign islet cell tumors may be higher. Detailed incidence data by time period, sex, and race are included in Table 1.
TABLE 1.Age-adjusted incidence rate of islet cell carcinoma per 100,000 populationaTime period and raceAllMaleFemaleSEER 9 (1973–1991)  All races.16 (.15–.18).19 (.17–.22).14 (.13–.16)  White.16 (.14–.17).19 (.16–.21).14 (.12–.16)  African American.25 (.19–.32).29 (.19–.43).22 (.16–.32)  Other.11 (.07–.18).16 (.09–.28).08 (.04–.16)SEER 13 (1992–1999)  All races.14 (.13–.16).17 (.15–.20).12 (.10–.14)  White.15 (.13–.17).18 (.15–.21).13 (.11–.15)  African American.11 (.07–.16).12 (.05–.25).10 (.06–.18)  Other.13 (.09–.18).18 (.11–.28).09 (.05–.15)SEER 17 (2000–2003)  All races.12 (.10–.13).12 (.11–.15).11 (.09–.13)  White.12 (.11–.13).14 (.12–.16).11 (.09–.13)  African American.14 (.09–.19).10 (.05–.20).16 (.10–.24)  Other.07 (.04–.12).03 (.01–.11).11 (.06–.18)a Rates are per 100,000 population (95% confidence interval) age-adjusted to year 2000 U.S. standard population. Cases were selected by ICD-O-3 histology codes 8150–8155, 8240–8245, and confirmed pancreatic primary site. Cases designated as poorly differentiated or anaplastic by grade were excluded. Cases of unknown race are excluded from the “other” category (included in “all races”).
Limited Duration Prevalence
Among the population sampled by the SEER 9 registries, 28-year limited duration prevalence for islet cell carcinoma on January 1, 2003, was estimated by the counting method to be 227 (95% CI, 199–259). These data were then projected to the general U.S. population. Data were matched by sex, race, and age to the U.S. standard population. The estimated 28-year limited duration prevalence of islet cell carcinomas on January 1, 2003, in the United States was 2705 cases. In comparison, the 28-year limited duration prevalence for all pancreatic neoplasms regardless of histology was 27,201.14 Thus, although islet cell carcinoma represented 1.3% of pancreatic cancer by incidence, it represented 9.9% of cases by the 28-year limited duration prevalence analyses.
Patient Characteristics
Of the 1310 patients with islet cell carcinoma identified in the SEER database, there were 619 women and 691 men. The majority (1095 cases) were white. African American and other racial groups accounted for 134 and 78 cases, respectively. Details of patient characteristics are included in Table 2. The other racial groups included American Indian/Alaskan Natives, and Asian/Pacific Islanders. In three cases, the race was unknown. We plotted the number of cases by age group at diagnosis in Fig. 1; the peak age distribution was 65 to 69 years. However, the median age at diagnosis was 59 years.
TABLE 2.Characteristics of 1310 patientsaCharacteristicValueSex, n (%)  Male691 (53)  Female619 (47)Race, n (%)  African American134 (10)  White1095 (84)  Other78 (6)  Unknown3 (.2)  Median (SD) age at diagnosis (y) 59 (15)ICD-O-3 groupings, n (%)  Islet cell1117 (85)  Insulinoma49 (4)  Glucagonoma29 (2)  Gastrinoma73 (6)  VIPoma16 (1)  Mixed histology26 (2)SEER stage, n (%)  Localized179 (14)  Regional295 (23)  Distant711 (54)  Unknown125 (10)Location of primary tumor, n (%)  Head379 (29)  Body103 (8)  Tail278 (21)  Overlapping108 (8)  Unknown442 (34)Year of diagnosis, n (%)  1973–1988482 (37)  1989–2003828 (63)a Cases selected from SEER 17 database by ICD-O-3 histology codes 8150–8155, 8240–8245, and pancreatic primary site. Cases designated as poorly differentiated or anaplastic by grade were excluded.FIG. 1.Age at diagnosis of 1310 cases of islet cell carcinoma. The median and mean (SD) ages at diagnosis are 59 and 58 (15) years.
We next examined the effect of race and sex on age at diagnosis. The median age in years at diagnosis for white, African American, and other racial groups was 60 (mean 58, SD 14.9), 55 (mean 54.5, SD 16.5) and 56 (mean 57, SD 16.5), respectively (P = .02, Fig. 2). However, there was no difference in median age at diagnosis based on sex.
FIG. 2.Age at diagnosis by race. White patients were older at the time of diagnosis (P = .02). The median age at diagnosis for white, African American, and other racial groups was 60 (mean 58, SD 14.9), 55 (mean 54.5, SD 16.5), and 55.5 (mean 57, SD 16.5), respectively.
Tumor Location and Hormone Production
The location of the primary tumors within the pancreas was described in 868 cases. In 442 cases, the detailed location data is not known. This is partially because the current coding system allows tumor location to be coded as islet of Langerhans, which gives no information about the location of the tumor within the pancreas. In 379 cases, the primary tumor was located in the head of the pancreas; body, tail, and overlapping groups accounted for 103, 278, and 108 cases, respectively.
By ICD-O-3 histology codes, 1117 cases (Table 2) were coded as islet cell or carcinoid (ICD-O-3 = 8150, 8240, 8241). Because these designations can include either serotonin-producing or nonfunctional tumors, it is not possible to determine the secretory status in these cases. Among the known functional tumors, gastrinoma was the most common with 73 cases (22 cases of duodenal gastrinoma not included); insulinoma, glucagonoma, and VIPoma accounted for 49, 26, and 16 cases, respectively. Finally, in 26 cases, the tumors were considered to have mixed endocrine/exocrine histology (ICD-O-3 = 8154, 8243–8245).
Next, we compared the location of the primary tumors within the pancreas by histological classification. We found significant differences in the pattern of primary tumor localization (P = .029); nonfunctional or serotonin-producing tumors (coded as islet cell and carcinoid tumors) were more likely to be located in the head (44%) than in the body (12%) or tail (31%) or overlapping (14%). Among the functional neoplasms, most insulinomas (57%), glucagonomas (53%), and VIPomas (64%) were located in the tail of the pancreas. Gastrinomas were much more likely to be located in the head of the pancreas (63%).
Tumor Stage
Of the 1310 cases, 125 (10%) were not staged (Table 2). For the remaining 1185 cases, 179 (14%) were localized; 295 (23%) were classified as regional; and 711 (54%) were classified as distant. When we compared stage by ICD-O-3 histology, we found that most carcinomas were metastatic at the time of diagnosis, including islet cell carcinomas (61%), insulinomas (61%), glucagonomas (56%), and gastrinomas (60%). A smaller percentage of VIPomas (47%) were metastatic (P < .001). This may be the result of the presence of massive diarrhea in VIPoma patients, which may bring them to medical attention earlier. The higher rate of metastases among insulinoma patients observed in this study is likely because most small insulinoma are considered benign and not reported to SEER. Next, we compared stage by tumor location and found that tumors located at the head of the pancreas trended toward a lower rate of distant disease (48% head vs. 57% body, 58% tail, and 60% overlapping) and a higher rate of regional disease (34% head vs. 27% body, 23% tail, 27% overlapping). However, the difference was not statistically significant (P = .063).
Survival
For survival analyses, we excluded 36 cases that were identified at autopsy or on the basis of death certificates only. The median overall survival for all 1274 remaining cases was 38 months (95% CI, 34–43). When compared by the log rank test, SEER stage predicted patient outcome (P < .001). The median survival for patients with localized, regional, and distant islet cell carcinoma was 124 months, 70 months, and 23 months, respectively (Fig. 3). One-year, 3-year, 5-year, and 10-year survival rates are listed in Table 3. The median survival for those cases that were not staged was 50 (95% CI, 34–66) months. Relative risk was calculated by Cox proportional modeling. Compared to the group with localized disease, patients with regional and distant disease had 1.56- and 3.50-fold of increased risk of death during the period (1973–2005) included in this study.
FIG. 3.Stage and survival of 1157 patients from the time of diagnosis. Median duration of survival of patients with localized (n = 167), regional (n = 289), and distant disease (n = 558) was 124, 70, and 23 months, respectively (P < .001).TABLE 3.Survival by SEER stageSEER stageMedian survival (mo) (95% CI)Survival rateHRP1 y5 y10 yLocal124 (80–168)88%71%52%1.00 (referent)<.001Regional70 (54–86)82%55%38%1.56 (1.17–2.07)Distant23 (20–26)65%23%9%3.50 (2.71–4.54)SEER, Surveillance, Epidemiology, and End Results Program; 95% CI, 95% confidence interval; HR, hazard ratio.
We then examined potential prognostic factors for survival duration that were based on data available from the SEER database. For these analyses, we stratified patients by stage. Patients with missing stage data were excluded from the analyses. When compared against the group designated as islet cell or carcinoid by ICD-O-3 histology codes, patients with gastrinoma (P = .001) and VIPoma (P = .044) had longer survival durations after adjusting for the effect of stage (Table 4), while the group with mixed histology experienced worse survival. The difference was not statistically significant, which is likely because of the small number of cases in this category.
TABLE 4.Cox proportional hazard analyses of potential prognostic factors adjusted for stageaParameterHR (95% CI)P valueICD-O-3 group  Islet cell1.00 (referent)  Insulinoma.935 (.64–1.37).728  Glucagonoma1.12 (.68–1.84).652  Gastrinoma.57 (.41–.80).001  VIPoma.44 (.20–.98).044  Mixed histology1.18 (.65–2.13).596Location of primary tumor  Head1.00 (referent)  Body.74 (.55–.98).037  Tail.82 (.67–1.01).056  Overlapping1.32 (1.01–1.72).041  Age as a continuous variable1.03 (1.03–1.04)<.001Age grouped by median  0–591.00 (referent)  60+2.16 (1.87–2.49)<.001Sex  Female1.00 (referent)  Male1.07 (.93–1.23).367Race  African American1.00 (referent)  White1.18 (.93–1.50).176  Other1.31 (.89–1.92).173Year of diagnosis  1973–19881.00 (referent)  1989–2003.79 (.68–.91).001a All analyses have been adjusted for Surveillance, Epidemiology, and End Results Program stage.
The location of the primary tumor may have a marked effect on the time of presentation (head tumors may obstruct the bile duct and cause visible jaundice) and resectability, as well as on surgical morbidity and mortality. Therefore, we next examined the prognostic role of the location of the primary tumor within the pancreas (Table 4). In our analyses, tumors located at the head of the pancreas were less likely to be associated with distant metastasis. The rates of distant metastasis for primary tumors located in the head, body, tail, and overlapping locations were 48%, 57%, 58%, and 60%, respectively. These differences were not statistically significant (P = .063). However, once adjusted for stage, primary tumor location in the pancreatic head was associated with a worse prognosis than the pancreatic body (P = .037). Similarly, tumors in the pancreatic head tended to be associated with worse survival compared with those in the pancreatic tail (P = .056); however, the difference was not statistically significant. Patients with primary tumors that were classified as overlapping had the worst prognosis (P = .041). In some cases, an overlapping lesion may indicate a larger primary tumor that covered a larger portion of the pancreas.
Age is found to be a predictor of outcome in a variety of malignancies. We examined the effect of age at diagnosis on overall survival stratified by stage (Table 4, Fig. 4). In the Kaplan-Meier analysis, we separated the patients into two groups on the basis of median age. We observed decreasing survival with increasing age (P < .001). Similarly, we also examined the effect of age as a continuous variable in Cox proportional hazard modeling and found increasing age to be a predictor of poor outcome (P < .001).
FIG. 4.Age and survival. For the <59 age group, the median survival durations for localized, regional, and distant disease were 282 (95% CI, 204–360) months, 114 (95% CI, 83–145) months, and 35 (28–42) months. For the 60+ age group, the median survival durations for localized, regional, and distant disease were 46 (95% CI, 20–72) months, 38 (95% CI, 24–52) months, and 13 (95% CI, 10–16) months (P < .001).
Next, we examined the survival duration of patients with islet cell carcinoma by year of diagnosis. There has been an improvement in survival over time. Whether analyzed as a continuous variable by Cox proportional hazard modeling or divided into discrete time durations, the observed difference was statistically significant (P = .001). Sex and race did not significantly affect survival. The details of these analyses are included in Table 4.
Finally, we performed multivariate survival analyses by Cox proportional hazard modeling. SEER stage, primary tumor localization, ICD-O-3 histology groups, and age at diagnosis were entered into the model. In multivariate analysis, the ICD-O-3 histology group was not a statistically significant predictor of outcome. All other variables retained statistical significance; the most important predictor of outcome was stage. Compared to patients with localized disease, patients with regional (HR = 1.44) and distant (HR = 3.40) disease had decreased survival duration. Location of the primary tumor within the pancreas (P = .032) and age at diagnosis (P < .001) also remained significant predictors of outcome (Table 5).
TABLE 5.Multivariate survival analysesParameterHR (95% CI)P valueStage<.001  Local1.00 (referent)  Regional1.44(1.05–1.99).026  Distant3.40 (2.53–4.67)<.001  Age as a continuous variable1.03 (1.02–1.04)<.001Location of primary tumor.032  Head1.00 (referent)  Body.81 (.60–1.08).146  Tail.87 (.71–1.07).175  Overlapping1.26 (.97–1.65).089ICD-O-3 group.186  Islet cell1.00 (referent)  Insulinoma.80 (.46–1.39).427  Glucagonoma1.08 (.57–2.02).822  Gastrinoma.70 (.47–1.04).077  VIPoma.39 (.12–1.22).105  Mixed histology1.38 (.73–2.59).322HR, hazard ratio; 95% CI, 95% confidence interval.
DISCUSSION
In order for us to make advances in the diagnosis and management of patients with islet cell carcinoma, we must improve our understanding of the epidemiology, natural history, and prognostic factors for this relatively rare disease. Because of the rarity of neuroendocrine carcinoma and the lack of a staging system, much of the information previously published has been based on case series and anecdotal experiences. In this study, we take advantage of the vast amount of data collected by the SEER Program to examine the largest series of islet cell carcinomas reported to date. To our knowledge, this study represents the only population-based study of islet cell carcinoma in published literature.
Prevalence is defined as the number people alive on a certain date in a population that ever had a diagnosis of the disease. In this study, the counting method15 was used to estimate prevalence from incidence and follow-up data obtained from the SEER 9 registries. Complete prevalence can be established by this method by using registries of very long duration. The SEER 9 registries have the longest follow-up duration and contain data suitable for prevalence analyses for the past 28 years. Given the longer survival duration often experienced by patients with neuroendocrine carcinoma, we report only limited duration prevalence data which may somewhat underestimate the complete prevalence. By incidence, islet cell carcinomas account for only 1.3% of all pancreatic cancers. However, because of the better outcome generally experienced by patients with islet cell carcinoma, they represent almost 10% of pancreatic cancers in prevalence analyses.
We acknowledge that analyses from the SEER registries underestimate the total number of patients with islet cell tumors. All cases from the SEER database were denoted to be malignant. Thus, it is likely that small, benign-appearing tumors were not included in the SEER registries (for example, insulinomas and small nonfunctioning tumors). Although histologic evidence of invasion of basement membrane defines malignant behavior for most epithelial malignancies, the definition of malignant behavior for pancreatic neuroendocrine neoplasms is more complex. In the absence of malignant behavior such as direct invasion of adjacent organs, metastases to regional lymph nodes or distant sites, it may be difficult to classify an islet cell tumor as benign or malignant. Pancreatic endocrine tumors are classified as benign, uncertain malignant potential, and malignant on the basis of size, the presence or absence of lymphovascular invasion, and the number of mitoses and Ki-67–positive cells by immunohistochemistry. However, there is a considerable overlap among these histopathologic features in benign and malignant neuroendocrine tumors and there is even heterogeneity within different areas of the same tumor. Many small islet cell tumors may have been considered benign or of unclear malignant potential and were excluded from the SEER registries. However, size is likely a function of when a tumor is diagnosed; left untreated, it is likely that most islet cell tumors will eventually grow locally into adjacent structures or soft tissues, and/or spread to distant organs. Therefore, outside of small insulinomas, all islet cell neoplasms should be considered potentially malignant. Thus, although the SEER registry data provide important information about malignant islet cell tumors, the extent to which it underestimates the frequency of smaller islet cell neoplasms is unknown. In our experience, even small islet cell tumors without clear evidence of invasion or metastasis at the time of initial surgical resection may recur and spread years later.
We found a wide distribution of age at diagnosis, with a median of 59 years. Separated by race, white patients were older at the time of diagnosis. When we compared stage by histologic type, we found that VIPomas were less likely to be metastatic at the time of diagnosis. Several findings may have contributed to this observation. One possible explanation is that VIPomas are generally associated with profound watery diarrhea, which may cause patients to seek medical attention earlier than if they had nonfunctional tumors. Second, as previously mentioned, small insulinomas and gastrinomas may have been considered benign (in the absence of invasion of adjacent organs, lymph node metastases, or distant metastases) and therefore not captured for analysis thereby enriching the population of study patients with metastatic functioning tumor.
In an earlier publication that was based on data from the SEER Program, Modlin et al.9 described the five-year overall survival of patients with carcinoid tumors to be 59.5% to 67.2%. The survival of patients with islet cell carcinoma seems less favorable. In the present study, we observed a median overall survival of 38 months. This is identical to the median survival observed in a large retrospective series of 163 cases from the University of Texas M. D. Anderson Cancer Center.16 The survival duration of patients with distant metastases was also similar (23 months in current study vs. 25 months in the M. D. Anderson series). We did, however, observe improvements in the outcome of patients with islet cell carcinoma over time. These improvements were observed among all SEER stage groups (data not shown), and are likely due in part to improvements in supportive care.
By multivariate survival analysis, we found that stage of disease, primary tumor location, and age at diagnosis were important predictors of outcome. The difference in survival by primary tumor location can be attributed to several possible factors. In this study, patients with tumors classified as having overlapping location had the worst outcome. This is likely because of the larger tumor size in this group. Tumor located at the head of pancreas may be diagnosed earlier because of hyperbilirubinemia resulting from biliary obstruction. This is suggested by our finding of a trend (nonsignificant) for a lower rate of metastastic disease at the time of diagnosis on the basis of tumor location in the pancreatic head. However, adjusted for stage, patients with a tumor located in the pancreatic head were more likely to have a worse outcome than patients with tumors located in the body or the tail of the pancreas. One possible explanation is that tumors arising in the pancreatic head are of greater malignant potential. For example, most insulinomas (57%), glucagonomas (53%), and VIPomas (64%) were located in the tail of the pancreas. Such functioning tumors were also associated with improved survival compared with nonfunctioning tumors. In addition, the fact that tumors in the pancreatic head are more likely to cause biliary obstruction (with a risk for cholangitis), invade the duodenum (resulting in hemorrhage or obstruction), or involve the peripancreatic mesenteric vasculature (resulting in pain, mesenteric foreshortening, and malabsorption) may contribute to local tumor morbidity which may influence survival duration. There is also likely to be a general tendency on the part of physicians to avoid surgical resection of the pancreatic head (pancreaticoduodenectomy or Whipple procedure) when faced with a large tumor or low volume metastatic disease. This is not the case with tumors in the body or tail of the pancreas that can be surgically excised with a distal pancreatectomy. However, it is the pancreatic head tumor that carries the greatest risk for tumor associated morbidity such as hemorrhage and biliary or gastric outlet obstruction.16 To what degree patients with pancreatic head tumors suffer morbidity and mortality from local disease progression rather than distant metastases cannot be determined from this data set.
Finally, increasing age at diagnosis was a predictor of poor outcome in our study. The differences in survival were seen across all SEER stage groupings. Certainly, pancreatic resection carries considerable operative risks and the medical comorbidities that are associated with advancing age may have precluded some patients from resection while increasing the risk to those taken to surgery. For patients with advanced disease, systemic chemotherapy often includes drugs that are considered toxic.17,18 For example, doxorubicin is recognized to be cardiotoxic, and streptozocin may cause worsening of diabetes. Thus, heart disease and diabetes which are more common among older patients may have limited the use of these drugs.
At present, surgery is the only curative treatment for islet cell carcinoma. Surgery should be recommended for most patients in whom cross-sectional imaging suggests that complete resection is possible.19 Although islet cell carcinoma has a better prognosis than adenocarcinoma of the pancreas, the disease remains incurable once multifocal unresectable metastatic disease exists. Although survival beyond 10 years has been described in the literature for some patients with metastatic disease, the survival duration for most with advanced disease is far shorter. Although streptozocin-based chemotherapy can induce objective response in 32% to 39% of patients,17,20 second-line treatment options are limited. Newer approaches such as peptide receptor radiotherapy, systemic agents targeting vascular endothelial growth factor, and mTOR are under development.
Optimal management of patients with islet cell carcinoma requires an understanding of the disease process and a multimodal approach. A better understanding of the molecular biology of this disease may lead to improved clinical models for predicting outcome and developing novel treatment strategies for this relatively rare but complex disease. Until then, an understanding of the natural history of the disease as provided herein is necessary to allow physicians and patients to accurately assess the risks and potential benefits of treatment alternatives that are based on the extent of disease and the age and performance status of the patient.

islet cell
epidemiology
survival
pancreatic endocrine tumor
neuroendocrine tumor