The theories and realities of port-site metastases:

The Theories and Realities of Port-Site Metastases: A Critical Appraisal Paul Ziprin, FRCS, Paul F Ridgway, BMedSci, AFRCSI, David H Peck, PhD, Ara W Darzi, MD, FRCSI, FRCS, FACS

by any new surgical technique. With colorectal cancer, it was first shown on cadavers that an adequate lymphadenectomy could be performed laparoscopically.9 Since then, comparative studies have shown no differences in the number of lymph nodes harvested by open or laparoscopic techniques,10 proximal and distal margins, or the length of specimen retrieved.11 In rectal cancer surgery, the radial margin is most important in predicting local recurrence. In a series of 12 patients undergoing laparoscopic abdominoperineal resection, it has been demonstrated that there was not a major difference in the radial margins when compared with a similar number of patients undergoing conventional surgery.10 For these reasons, laparoscopic surgery for colorectal cancer achieves a similar oncologic standard as open operation and might have systemic biologic advantages.

Since Mouret performed the first laparoscopic cholecystectomy in 1987, this technique has become the gold standard for the management of cholelithiasis. With the assumption that the benefits of laparoscopic cholecystectomy could be applied more widely, laparoscopic surgery has been used in the operative management of different surgical pathologies, both benign and malignant. Endoscopic surgery has been widely described in both the staging and treatment of gastrointestinal, urogynecologic, and lung cancers, with laparoscopic colorectal procedures being perhaps the most widely performed and reported. For laparoscopic surgery to be an accepted method in the surgical management of cancers, it must fulfill a number of parameters. It must be as safe as or safer than conventional open operation, as evidenced by operative morbidity and mortality. Additionally, benefits in terms of length of hospital stay, postoperative pain, and cost are also desirable. To date, a number of studies have shown a benefit of reduced pain scores after laparoscopic colectomy,1,2 shorter postoperative ileus,1,3,4 and shorter hospital stay1-3,5 after laparoscopic colectomy. These benefits might be related to the reduced access-related trauma, as seen by a decreased cytokine response after laparoscopic colorectal resection.6 Similar attenuation of interleukin-6 response after thoracoscopic surgery has also been observed.7 But, with integrated care pathways, hospital stay after open colonic resection can be reduced to 2 days,8 indicating that the differences shown in other studies might not be so clear cut. Basic oncologic principles must not be compromised

The hypothesized oncologic benefits of laparoscopic surgery The use of minimal access techniques in the surgical management of cancer should be beneficial in terms of the oncologic effect on the tumor, compared with conventional surgery. Laparoscopic surgery attenuates the cytokine response observed after open operation, as measured by interleukin-6, and it has been shown that this cytokine potentiates tumor growth12 and the metastatic process.13 Murthy and coworkers14 demonstrated that surgical injury promotes tumor growth, and another group showed that reducing peritoneal trauma resulted in a decrease in tumor cell implantation.15 Consensus opinion dictates that laparotomy also enhances tumor growth, compared with laparoscopy in animal models.16,17 Gutt and coworkers18 and others have reported results to the contrary,19 but these authors have not been able to repeat this finding in other studies.20,21 Despite this evidence, use of these minimal access techniques in the surgical resection of malignant disease has not been taken up with great enthusiasm by surgeons. This is in part because of the process of learning a

No competing interests declared.

Received March 5, 2002; Accepted March 29, 2002. From the Department of Surgical Oncology and Technology, Faculty of Medicine, Imperial College of Science Technology and Medicine, St Mary’s Hospital, London, United Kingdom. Correspondence address: Paul Ziprin, FRCS, Department of Surgical Oncology and Technology, Imperial College of Science Technology and Medicine, St Mary’s Hospital, 10th Floor QEQM Building, Praed Street, London W2 1NY, UK.

© 2002 by the American College of Surgeons Published by Elsevier Science Inc.

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Figure 1. Port-site metastases (arrows) after laparoscopic cholecystectomy for previously undiagnosed gallbladder carcinoma.57 (Reproduced with permission of Blackwell Science Ltd, UK.)

more technically demanding method with reduced tactile feedback22 and initially longer operating times, but also, and more important, because of concerns over the incidence of port-site metastases (PSMs) soon after potentially curative surgery. Port-site metastases Dobronte and coworkers23 were the first to describe metastases at the port site 2 weeks after diagnostic laparoscopy for malignancy. These PSM occurred in patients with advanced disease, but since the early 1990s there have been many reports of early port-site and peritoneal recurrences after laparoscopic or thoracoscopic treatment of potentially curable cancer. PSM have occurred after laparoscopic cholecystectomy (Fig. 1)24 and after laparoscopic surgery for carcinoma of the pancreas,25,26 esophagus,27 colon, stomach,28 and liver29; for endometrial,30,31 fallopian tube,32 ovarian,33-36 and cervical cancer;30,34,37-40 and for bladder41 and renal tumors42-44 and a retroperitoneal liposarcoma.45 PSM have also been described after thoracoscopic surgery for esophageal46,47 and lung cancers.48-52 Most of these cases have occurred after surgical resection, but PSM have occurred without apparent manipulation of the tumor.53,54 Incidence of port-site metastases Alexander and coworkers55 reported in 1993 the occurrence of PSM 3 months after a curative right hemicolectomy for a Duke’s C colonic adenocarcinoma, and this

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phenomenon was confirmed by further reports of early port-site recurrences after potentially curative laparoscopic procedures for colorectal cancers.56,57 This problem does not appear to be exclusive to more advanced tumors, because there have been at least three reports of PSM after laparoscopic resection of Duke’s A cancers.58,59 There have been many reports of PSM after laparoscopic cholecystectomy for preoperatively undiagnosed carcinoma of the gallbladder. Paolucci and coworkers60 surveyed 443 hospitals in Europe and showed that of 409 cases of incidental gallbladder cancer, 70 (17.1%) developed at least one PSM at a median of 6 months postoperation. A similar finding was described by Lundberg.24 Patients undergoing laparoscopy for ovarian cancer also had a 16% PSM rate,61 but all these patients had advanced disease (this was not the case in the paper of Paolucci and coworkers,60 in which 26 patients had either in situ or T1 disease). Of note, a recent review of patients who underwent open cholecystectomy for gallbladder cancer showed wound recurrence rates of 6.5%.62 Wexner and Cohen63 in 1995 reviewed the literature about the incidence of PSM in colorectal cancer. They calculated the incidence by comparing the number of reported cases of PSM with the estimated number of laparoscopic colorectal cancer cases reported in the literature and presented at meetings at that time. They estimated that the incidence of PSM was 4%, with a range of 1.5% to 21% and a mean interval to recurrence of 7.2 months. This compares unfavorably with the incidence of wound metastases after conventional open operation. Hughes and coworkers64 described 11 patients of 1,603 who developed wound recurrences, an incidence of 0.69%, and a similar rate was observed by Reilly and coworkers.65 Other, albeit smaller, studies have demonstrated higher rates of wound metastases, ranging from 1.4% to 3.3%.66-70 One postmortem study by Welch and Donaldson71 revealed a wound metastasis rate of more than 16%, although these cases were all associated with disseminated disease. Although PSM have been observed to occur early after surgical intervention, wound recurrences are not unique to laparoscopic surgery. There have been fewer reports of PSM in the literature more recently. Table 1 summarizes the results of published series of more than 50 patients undergoing laparoscopic colorectal operations for cancer with regard to the frequency of PSM. The overall incidence of PSM is only

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Table 1. The Incidence of PSM Based on Studies with Samples of at Least 50 No. of PSM as sole disease First author

Year

Guillou72 Boulez73 Franklin74* Fleshman75 Gellman76 Kwok77† Vukasin78 Hoffman79 Lacy80 Larach81 Fielding82 Croce83 Bouvet84 Khalili4 Leung85 Bohm86 Poulin87 Pearlstone88 Melotti89 Hartley90 Schiedeck91 Gibson92‡ Lezoche93§ Kockerling94 De Mulder95 Hong96 Lauter97 Total

1993 1996 1996 1996 1996 1996 1996 1996 1997 1997 1997 1997 1998 1998 1999 1999 1999 1999 1999 2000 2000 2000 2000 2000 2001 2001 2001

Total no. of PSM

Sample size

n

%

n

%

57 117 191 372 58 83 451 130 106 108 149 173 91 80 154 63 172 93 163 57 399 193 113 116 86 98 69 3,942

0 3 0 3 0 0 3 0 0 0 0 1 0 0 0 0 0 0 1 0 1 0 1 0 0 0 0 13

0 2.5 0 0.8 0 0 0.7 0 0 0 0 0.6 0 0 0 0 0 0 0.6 0 0.3 0 0.9 0 0 0 0 0.33

1 3 0 4 1 1 5 1 0 0 2 1 0 0 1 0 0 0 2 1 1 2 2 0 0 0 0 28

1.8 2.5 0 1.1 1.6 1.2 1.1 0.8 0 0 1.4 0.6 0 0 0.6 0 0 0 1.2 1.8 0.3 1.0 1.3 0 0 0 0 0.71

*A subsequent paper from this author98 assessed outcomes of 50 patients with stage III disease after laparoscopic surgery, and again there were no PSM. † This was a wound recurrence in the abdominal wound through which the specimen was retrieved in a patient undergoing a palliative right hemicolectomy. ‡ This includes one patient who developed an incisional recurrence after conversion to an open colectomy. § These PSM developed during the first 33 laparoscopic procedures, but none were found in the subsequent 80 patients, after employment of preventive measures. PSM, port-site metastases.

0.71%. A much lower incidence of 0.33% is observed if one examines only those patients with trocar recurrences as the sole finding, without any other evidence of metastatic disease, indicating that this phenomenon is a rare event. Although some of these reports were prospective studies, none were part of a randomized controlled trial comparing laparoscopy with open techniques. Lacy and coworkers99 have published a randomized controlled study comparing open and laparoscopic resection of colonic malignancies with only 47 and 44 patients in the respective groups. Both groups had similar recurrence rates, and there were no incidences of wound or PSMs in either group. Recently, at the 2001 SAGES Meeting in

St Louis, it was reported that there had been no PSM seen in the ongoing National Cancer Institute prospective, randomized controlled trial comparing laparoscopic and open colectomy.100 To participate in this study, surgeons have to have performed at least 20 laparoscopic colorectal procedures and to have had their technique peer reviewed. Based on these criteria, all participating surgeons are deemed to have a satisfactory technique and level of laparoscopic experience. Similarly, the Medical Research Council-sponsored Conventional Versus Laparoscopic-Assisted Surgery for Colorectal Cancer Trial in the United Kingdom has not had to be halted because of an unacceptable PSM rate.

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Table 2. Potential Mechanisms for the Development of PortSite Metastases Hematogenous spread Direct wound implantation Extraction of specimen Instrument contamination “Chimney effect” Aerosolization of tumor cells Surgical technique Excessive tumor manipulation Surgical experience Effect of the pneumoperitoneum Pressure Effect of CO2 Impairment of the host local immune response

for the differences observed in the incidence of PSM, unless the ports themselves inflict a greater local insult, which as previously stated will enhance tumor growth, or there are other specific factors peculiar to laparoscopy or thoracoscopy that might enhance tumor implantation. The former hypothesis is supported by work published by Tseng and coworkers,106 who demonstrated that tissue trauma at trocar sites enhances tumor implantation. The latter assumption will be discussed in more detail later.

Prognostic significance of port-site metastases Does the occurrence of PSM have an impact on survival? Kruitwagen and coworkers101 showed that after adjustment for age, International Federation of Gynaecologists and Obstetricians (FIGO) stage, histology, grade, ascites, and residual disease after primary debulking, there was a negative correlation between PSM and survival. Also, the 2-year survival rate for patients with PSM from gallbladder cancer was found to be 18.5%,60 which compares unfavorably with gallbladder cancers diagnosed after open cholecystectomy.102,103 Pathogenesis of port-site metastases Table 2 summarizes the postulated etiologies of PSM. Trocar recurrences have occurred after four different scenarios: 1) after laparoscopic cholecystectomy for an occult gallbladder or other gastrointestinal cancer, 2) after laparoscopic or thoracoscopic surgery in patients undergoing palliative treatment for advanced cancer, 3) after resection for potentially curable malignant disease, and (perhaps most interesting of all) 4) subsequent to diagnostic or staging procedures when there has been no disturbance of the primary tumor. It is with this knowledge that the theories concerning the pathogenesis of this problem will be discussed. Hematogenous spread In discussing the possible mechanisms that might account for this phenomenon of PSM, one must consider both systemic and local factors. It has been shown that localized tissue trauma has enhanced the implantation of circulating tumor cells,104,105 but this would not account

Direct wound implantation It is more likely that direct implantation of tumor cells into the wound is likely to play a major role in the development of PSM. Events occurring early after injury appear to be important in tumor implantation, as evidenced by the facts that tumor adhesion and growthpromoting factors are active within 5 hours of surgery and that the frequency of tumor implantation at the site of injury decreases with time.15 Extraction of the tumor through the port site can lead to tumor cell deposition in the wound, especially if traumatic manipulation of the surgical specimen is required to pull it through a relatively small access wound. Of those patients who developed PSM after laparoscopic cholecystectomy for unknown gallbladder carcinoma, 55% of PSM were found at the port used for the extraction of the gallbladder.60 Also, in an animal model, Bouvy and coworkers107 showed that the size of abdominal wall metastases was greater at the port site of extraction of the tumor than at the other port sites. These data do not explain the 40% of recurrences after laparoscopic cholecystectomy for occult gallbladder cancer that occurred at other port sites, nor do they explain those that occurred at the extraction port after removal of the specimen in a protective bag. Instrument contamination Other mechanisms must also exist to account for these cases. Patients with advanced disease, for example, those with stage III colorectal cancers, are at higher risk of having free IP cells. Investigators have shown that these free IP cells are both viable and demonstrate metastatic potential,61,108 and these cells can be transported to the port sites. It has been demonstrated that during operation, both the instruments and trocars can become contaminated with viable cells. Doudle and coworkers109 found gallbladder mucosal cells on instruments at the

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end of surgery in 6 of 15 patients undergoing laparoscopic cholecystectomy, and both instruments and ports were contaminated by tumor cells in other studies using animal models.110,111 Lead surgeons’ port wounds have also been found to be contaminated with more tumor cells than either those of the assistants or the port through which the laparoscope was used.110 Repeated removal of contaminated instruments through the port sites or increased manipulation of trocars might enhance tumor cell inoculation. Allardyce and coworkers112 later produced evidence supporting this theory by showing in a porcine model that tumor cell implantation was augmented at wounds after increased manipulation of the ports.

have also failed to demonstrate aerosolization of tumor cells in both in vitro and in vivo studies.112,116-118 Kim and coworkers119 investigated whether laparoscopy increased the number of exfoliated cancer cells in patients undergoing laparoscopic colectomy, compared with a control group of patients undergoing open operation. This study did not detect any differences between the two groups and concluded that when surgery is performed according to strict oncologic principles, laparoscopy did not increase IP cancer cell spillage, compared with conventional surgery. Even if aerosolization plays a role in the development of PSM, it does not explain the incidence of early port recurrences in thoracoscopic surgery, during which gas insufflation is not required, nor does it explain recurrences after resection for Duke’s A or B colorectal lesions.

Chimney effect Indirect contamination of trocar wounds has also been suggested as a cause of PSM such as the “chimney effect.” This suggests that tumor cells are preferentially translocated to port sites because of microleakages around the trocars. Again, this requires the presence of free IP cells. Using a porcine model, Allardyce and coworkers112 were able to filter tumor cells out from the insufflation gas escaping at port sites not only where leaks had been intentionally created, but also at port sites where the instruments had been used vigorously. Only a minimal amount of cells was recovered from the exhaust that was produced when trocars were deliberately vented. Also, Tseng and coworkers106 demonstrated increased tumor growth at port sites where leaks had been induced, but the size of periportal leak used in this model is perhaps not representative of the clinical situation. Tumor cell aerosolization Hewett and coworkers113 demonstrated increased tumor cell movement with a carbon dioxide (CO2) pneumoperitoneum compared with gasless laparoscopy, although Allardyce and coworkers112 showed that the use of gasless laparoscopy did not eliminate contamination of the wound by tumor cells. Another study demonstrated the presence of blood and mesothelial cells in the diathermy smoke created during a laparoscopic procedure.114 The viability of aerosolized tumor cells is obviously of crucial importance, and various investigators have suggested that this is unlikely. Nduka and coworkers115 found that cells released during electrosurgical dissection in an animal model were not viable, and others

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Surgical technique Both clinical and experimental data suggest that poor surgical technique during the development of advanced laparoscopic procedures might have contributed to the number of case reports of PSM. For example, differences in surgical technique or skill can account for the considerable variability in outcomes from colorectal cancer between surgeons in terms of morbidity, local control, and survival.120,121 Also, improved outcomes from colorectal surgery have also been documented in specialist units.122 Studies reporting high PSM rates included small patient numbers, but the learning curve for performing laparoscopic colorectal surgery might be as high as 70 operations, as judged by operating time, length of hospital stay, complications, and conversion to open operation.123-126 This might account for the apparently high incidence in earlier reports, compared with larger series, but oncologic results were not an outcomes measure in these studies. Intraoperative spillage of tumor cells has been demonstrated by comparing peritoneal lavage fluid cytology at the start and end of surgery after potentially curative surgery,108,127,128 and this will reduce 5-year survival notably.129 In a model consisting of the establishment of a splenic tumor after the subcapsular injection of colonic adenocarcinoma cell line, Lee and coworkers130 produced evidence supporting the role of surgical technique in the incidence of PSM. They demonstrated that traumatic handling of the tumor enhanced wound implantation, and this was independent of the pneumoperitoneum. This has been confirmed by another study that

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also demonstrated that this enhancement was further perpetuated by laparotomy, compared with laparoscopy.17 Lee and coworkers131 further showed that the incidence of PSM after laparoscopically assisted resection of the spleen decreased to a level comparable with that of open operation with increasing experience of the operator as the experiment progressed. This would seem to suggest that adherence to strict surgical oncologic principles together with surgical experience are the most important factors in avoiding the development of PSM. There have been a number of reports of PSM after laparoscopic staging of malignancy when there has been no manipulation of the tumor53,88 and also after routine laparoscopic cholecystectomy in the presence of an undetected colonic tumor.54 This would suggest that the causes of PSM are multifactorial and can also be caused by the pneumoperitoneum itself.

The effect of pressure on port-site metastases Jacobi and coworkers139 investigated the effect of different pressures on tumor growth and PSM rate using both in vitro and in vivo models. They demonstrated that in vitro tumor growth decreased substantially after incubation with CO2 at 10 and 15 mmHg, compared with pressures of 0 and 5 mmHg. Using the in vivo model, IP tumor weight was notably increased after laparoscopy at 5 mmHg and at 10 mmHg, compared with a pressure of 0 mmHg, but tumor growth was again suppressed at a pressure of 15 mmHg. On the other hand, Gutt and coworkers140 found that the effect of different pressures on tumor growth in vitro varied between two cell lines. The proliferation of a colon cancer cell line was increased at higher pressures, but the growth of a pancreatic adenocarcinoma was independent of the insufflation pressure. Another study showed enhanced peritoneal tumor growth with an insufflation pressure of 16 mmHg, compared with 4 mmHg in a rat model,141 and Ishida and coworkers142 demonstrated that higher pressures increased pulmonary tumor deposits after IV tumor cell inoculation. The traumatic effect of such high pressures in a small rodent makes it questionable whether this effect translates to the clinical setting.

The role of the pneumoperitoneum in the development of port-site metastases Although several animal studies have shown that laparotomy enhances tumor growth, compared with laparoscopy,16,17,132 there have been many published studies investigating the effect of the laparoscopic environment on tumor growth and PSM. Initial observations made by Bouvy and coworkers107 showed that laparoscopy with CO2 pneumoperitoneum resulted in increased tumor growth and greater port-site and abdominal wall metastases, compared with gasless laparoscopy in both a cell-seeding and a solid tumor model. A number of other animal studies have also shown that laparoscopy with CO2 increased IP tumor growth and the incidence of PSM when compared with gasless laparoscopy19,20,133 or helium pneumoperitoneum.134-136 An air pneumoperitoneum has not conferred any benefit over the use of CO2.135 This apparent effect of CO2 does not appear to be limited to IP growth, because CO2 laparoscopy has also been shown to enhance the growth of subcutaneous tumors137 and to enhance the development of hepatic metastases.20,138 Two conclusions can be drawn from these studies. First, the pressure of the pneumoperitoneum might play a role, because CO2 laparoscopy appears to have a detrimental effect on tumor growth compared with gasless laparoscopy, and second, CO2 might also contribute to development of PSM, because this insufflation gas enhances peritoneal tumor growth compared with helium.

The effect of CO2 on tumor cell biology CO2 is the most commonly used insufflating gas in laparoscopic surgery, and it has been postulated that this gas itself might promote tumor growth and increase the metastatic potential of the tumor cell. As previously described, a number of studies show that exposure to a CO2 pneumoperitoneum increases PSM and IP growth in animal models, compared with helium insufflation.134-137 Nduka and coworkers115 produced further evidence directly incriminating CO2; they demonstrated with a cell-seeding model that rats that were injected with tumor cells previously exposed to CO2 or helium developed more wound and peritoneal tumor deposits than those injected with cells kept in standard culture conditions. Jacobi and coworkers143 investigated the effect of an in vitro CO2 pneumoperitoneum on tumor cell growth using a rat colonic adenocarcinoma cell line. They demonstrated that CO2 directly enhanced the cell growth of this cancer cell line. Neuhaus and coworkers144 showed that helium inhibited the growth of a rat mammary adenocarcinoma cell line when compared with cells exposed to CO2 or control conditions. On the other hand,

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we have found that neither CO2 nor helium enhances or impairs tumor cell viability or proliferation, compared with cells kept in standard culture conditions.145 This is supported by Dorrance and coworkers,146 who found that laparoscope-enhanced IP tumor growth was independent of the insufflating gas that was used. Those experiments that showed a deleterious effect of CO2 on tumor growth led to a number of studies that investigated the effect of the laparoscopic environment on tumor cell biology. It was first noted that exposure to an in vitro pneumoperitoneum decreased homotypic cell adhesion and cell–cell matrix adhesion using a human colonic adenocarcinoma cell line.147 This was then subsequently shown to be associated with decreased expression of a number of important cell adhesion molecules, such as ␤-1 integrin subunit, CD44, and E-cadherin.148 Also, it was found that the pneumoperitoneum causes an enhancement in the ability of tumor cells to invade through a reconstituted basement membrane, and this appears to be because of an upregulation in matrix metalloprotease activity,145 plasminogen activator activity, and urokinase plasminogen activator receptor expression.149 Further work demonstrated that the adhesion of tumor cells to the peritoneum in vitro was increased after the mesothelial cell monolayer had been exposed to a pneumoperitoneum.150 Yamaguchi and coworkers151,152 hypothesized that enhanced peritoneal tumor growth can be caused by increased hyaluronic acid secretion by the mesothelial cells.

that the differences in immune suppression are related to differences in incision length. On the other hand, local peritoneal immune responses might account for the enhanced tumor growth observed after CO2 laparoscopy, compared with gasless or helium. Neuhaus and coworkers158 showed that the immune system did play a role in tumor growth. They demonstrated that priming the immune system with endotoxin before tumor cell inoculation reduced tumor growth. In an in vitro system, West and coworkers159 found that exposure of peritoneal macrophages to CO2 resulted in impaired tumor necrosis factor alpha secretion in response to stimulation with lipopolysaccharide, compared with macrophages exposed to air or helium. This observation was confirmed by others.160,161 In addition to this, a study from our institution showed that the ability of macrophages to kill tumor cells was also impaired after exposure to CO2.161 Using an animal model, Mathew and coworkers162 demonstrated that the increased tumor growth after exposure to CO2 was related to impaired macrophage function. The cause of these changes is most likely related to the production of a hypoxic environment. Wildbrett and coworkers163 examined the effects of different laparoscopic gases on submesothelial oxygen tensions and showed that both CO2 and helium decreased tissue oxygen partial pressure from 23 mmHg to 5 mmHg and from 25 mmHg to 6.5 mmHg, respectively. In the studies discussed earlier, CO2 appears to have a greater effect than helium on tumor progression, which might be because of differences in the pH of the environment that is produced. Indeed, Kuntz and coworkers164 showed that laparoscopy with CO2 decreases the subcutaneous pH from 7.35 to 6.81 and the intraabdominal pH from 7.35 to 6.24, compared with helium or air, both of which had relatively little effect. This change in pH was also dependent on the insufflation pressure.

Laparoscopy and the host immune response Compared with open operation, laparoscopy results in a reduced inflammatory response as measured by the cytokines interleukin-6 and C-reactive protein.6,153 This might account for the enhanced tumor growth after laparotomy observed in animal studies.16,132 This also reflects the influence of operation on the immune response. Both large- and small-animal studies have shown better preservation of delayed-type hypersensitivity immune response after laparoscopic procedures,154,155 and this is probably related to reduced surgical trauma from smaller incision. Allendorf and coworkers156 showed that immune suppression after operation was directly proportional to the degree of surgical trauma by comparing the effect of laparotomy, minilaparotomy, and laparoscopy, and this effect was independent of gas type. Lee and coworkers157 also found no differences between air and CO2 on lymphocyte proliferation and so deduced

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Limitations of in vivo and in vitro models There are great differences among the studies that have been published in this field. They differ in terms of animal model and tumor cell line used, study design, size of tumor inoculum, duration and pressure of the pneumoperitoneum, time course of study, and assessment of tumor growth. A paper from Gutt and coworkers140 best illustrates the influence of different cell lines on outcomes. They observed that different insufflation pressures in vitro influenced the proliferation rate of a co-

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Table 3. Strategies in the Prevention of Port-Site Metastases Retrieval bags for specimens Wound protectors Use of intraperitoneal agents Heparin Taurolidine Iodine 5-fluorouracil Doxorubicin Use of alternative insufflating strategies Helium Gasless laparoscopy Port-site excision Peritoneal wound closure

lonic cancer cell line, but had no effect on a pancreatic cell line. Most studies use small-animal models, with which larger studies are more easily performed, but perhaps the use of large-animal models such as pigs would best match the clinical situation. The cell-seeding or suspension model is probably the most common animal model used for the investigation of the pathogenesis of PSM, but there are concerns about the relevance of this model. It makes a number of assumptions, for example, that free IP cancer cells are present and viable and also that the tumor inoculum used in these studies is representative of the clinical situation. Umpleby and coworkers61 recovered tumor cells, of which 92% were viable, in lavage fluid from 14 of 19 patients undergoing colonic resection for malignancy, with a median number of cells of 0.78 ⫻ 106. Based on this observation, many studies have used between 105 and 108 cells, but the small size of the animal models used in many of these studies, compared with humans, might result in an exaggerated response. Indeed, Wu and coworkers165 have shown that a pneumoperitoneum in a hamster model did not enhance PSM rate after a tumor inoculum of 1.6 ⫻ 105 cells, but IP injection of double the quantity of cells did demonstrate a difference, showing that the development of PSM was dependent on the amount of tumor cell inoculum,165 and others have also shown that outcomes are also affected by the size of the tumor inoculum.112 With the cell-seeding model, cells are inoculated into the recipient animal in culture medium that can sustain the viability of the tumor cell, resulting in enhanced tumor implantation at the trocar site. Although it has been shown that IP tumor cells are viable,61 their long-

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term ability to implant and proliferate might not match that of cells supplemented by culture media. Solid tumor models would be more appropriate in the investigation of the impact of laparoscopic surgery on PSM. Models have been used in which solid pieces of tumor are placed in the abdominal cavity during the course of the surgical procedure and then removed. Other various solid tumor models used include those produced after subcutaneous inoculation135 and renal subcapsular166 or intrasplenic167 injection of tumor cells, and these models might not be appropriate for the study of the etiology of PSM, although a solid model of colorectal cancer has recently been described.168 A number of studies have also investigated the effect of tumor manipulation on PSM rates,17,130 although it is difficult to control for and quantify the amount of tumor cell spillage. Different pressures have been used in both in vivo and in vitro studies investigating the etiology of PSM. Pressures as high as 15 mmHg have been used in some smallanimal studies. Although this might be compatible numerically with laparoscopy clinically, the physiologic effects of such a pressure on a small animal cannot be comparable. Gutt and coworkers169 studied the effect of a pneumoperitoneum on portal vein flow in rats and concluded that the physiologic and hemodynamic changes observed at pressures of between 6 and 8 mmHg in a rat were comparable to those seen in humans at a pressure of 15 mmHg. So although studies using both laboratory-based and animal models have shown the potential harmful effect of the pneumoperitoneum on the development of PSM, it has to be understood that these have inherent limitations that might affect their validity. Peevention of port-site metastases A number of investigators have studied various preventative measures to reduce the incidence of PSM (Table 3) despite the significance of PSM’s being inconclusive. It must be emphasized that these strategies cannot replace the use of robust oncologic techniques during operation, in particular avoidance of traumatic manipulation of the tumor. It has been suggested that the use of bags for the retrieval of specimens during surgery might decrease the risk of wound implantation by tumor cells.74 Doing so might not prevent all cases of PSM, as illustrated by the data collected by Paolucci and coworkers60 concerning PSM after laparoscopic cholecystectomy.

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Locoregional administration of tumor static agents might have a role to play in diminishing the biologic effects of the pneumoperitoneum on tumor cells. Matrix metalloprotease inhibitors might have a role and have been shown to attenuate increased invasive tendencies in vitro.128 IP heparin has been demonstrated to reduce the incidence of peritoneal and wound recurrence rates in animal models,170,171 but trocar wound instillation of heparin appears to have no effect.172 Using a cell suspension model, Jacobi and coworkers173 showed that the use of IP taurolidine reduces trocar metastases in a rat, and this effect was enhanced when taurolidine was used in combination with heparin. The use of povidone iodine and chemotherapeutic agents such as 5-fluorouracil or doxorubicin has been shown to reduce the incidence of PSM.170,172,174,175 Different surgical approaches have been shown to influence the development of PSM. It has been demonstrated that gasless laparoscopy might offer advantages in terms of trocar recurrences,107,133 but the use of gasless laparoscopy has not become widespread because of the poor surgical access afforded by current instruments. As discussed previously, the use of an alternate gas such as helium might offer advantages over CO2.134,136 Wu and coworkers176 reduced the incidence of PSM by excising the trocar wounds at the end of the procedure, but this might reduce any benefits that minimal access techniques bring to surgery. Others have suggested that closure of the peritoneum might also be beneficial.177

Author Contributions: Study conception and design: Ziprin, Darzi Acquisition of data: Ziprin, Peck, Ridgway, Darzi Analysis and interpretation of data: Ziprin, Ridgway, Peck, Darzi Drafting of manuscript: Ziprin, Ridgway, Peck, Darzi Supervision: Ziprin, Darzi

CONCLUSIONS In conclusion, the initial high rates of early trocar wound and peritoneal recurrences led to obvious concerns about the use of minimal access techniques in oncologic surgery. Even though experimental data on the whole support the theories that laparoscopy, in particular the CO2 pneumoperitoneum, might have a detrimental effect on IP tumor growth, this phenomenon is not as common as first thought, and the true incidence might be in keeping with that seen after open operation. This fact, together with the other clinical and experimental data, suggests that the reality is that poor surgical technique, such as improper handling of the tumor, is the likely cause of this phenomenon. The results of ongoing randomized trials will answer whether PSM is a true phenomenon of laparoscopic surgery.

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