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Original Article |

Protective Covering of Surgical Wounds With Honey Impedes Tumor Implantation FREE

İsmail Hamzaoglu, MD; Kaya Saribeyoglu, MD; Haydar Durak, MD; Tayfun Karahasanoglu, MD; İbrahim Bayrak; Tuncay Altug, MD; Feridun Sirin, MD; Muzaffer Sarıyar, MD
[+] Author Affiliations

From the Departments of Surgery (Drs Hamzaoglu, Saribeyoglu, Karahasanoglu, Sirin, and Sariyar), Pathology (Dr Durak), and Medical Biology (Mr Bayrak), and the Experimental Animal Research and Production Laboratory (Dr Altug), Cerrahpa[[scedil]]a Medical School, [[Idot]]stanbul, Turkey.


Arch Surg. 2000;135(12):1414-1417. doi:10.1001/archsurg.135.12.1414.
Text Size: A A A
Published online

Hypothesis  Tumor implantation (TI) development at the surgical wound following cancer surgery is still an unresolved concern. Trocar site recurrence, which is likely a form of TI, has become one of the most controversial topics and, with the widespread acceptance of laparoscopic surgery, has caused renewed interest in questions about TI. Honey has positive effects on wound healing. Physiological and chemical properties of honey might prevent TI when applied locally.

Design, Interventions, and Main Outcome Measures  Sixty BALB/c strain mice, divided into 2 groups, were wounded in the posterior neck area. Group 1 mice formed the control group, and group 2 mice had wounds coated with honey before and after tumor inoculation. All wounds were inoculated with transplantable Ehrlich ascites tumor. The presence of TI was confirmed in the wounded area by histopathological examination on the 10th day.

Results  Tumor implantation was achieved in all group 1 animals and verified by palpable mass and histopathological examination. In group 2 mice, although TI could not be detected macroscopically, it was revealed by pathological examination in 8 cases. Tumor implantation was less likely in group 2 mice (8 of 30 vs 30 of 30; P<.001).

Conclusions  Tumor implantation was markedly decreased by the application of honey pre- and postoperatively. It is possible that the physiological and chemical properties of honey protected wounds against TI. Honey could be used as a wound barrier against TI during pneumoperitoneum in laparoscopic oncological surgery and in other fields of oncological surgery.

Figures in this Article

TUMOR IMPLANTATION (TI) is a complex phenomenon still under study. Mechanisms and preventive measures are subject to investigation. After the first report1 concerning trocar site recurrence (TSR), there was concern about the increased incidence of TI associated with laparoscopic oncological surgery. Although numerous experimental studies28 showed an increased incidence of TSR, clinical trials911 did not confirm this finding. In any case, reports of TSR diminished the widespread use of laparoscopy in malignant disease and evoked the concern of TI once more.

Honey has long been used to accelerate wound healing.1214 Physiological properties of honey such as hypertonicity, low pH, and hygroscopicity were thought to augment the healing process. Antibacterial effects were also attributed to these elements. Moreover, tumoricidal effects are associated with chemical compounds such as caffeic acid esters, which are present in honey.15,16

We hypothesized that the protective covering of wounds with honey may provide protection against TI by forming a tender film barrier, which could inhibit the attachment of tumor cells to the wound.

In this study, a reproducible wound model was designed by creating an air sac in the posterior nuchal area of BALB/c mice to investigate the role of a honey barrier against tumor cell invasion.

ANIMALS

Sixty BALB/c mice, 7 to 8 weeks old and weighing 20 + 3 g (mean + SD), were divided into 2 groups. Group 1 mice formed the control group and group 2 mice had wounds coated with 1 mL of commercial honey via a 14-gauge cannula before and after tumor inoculation. Subcutaneous air sacs were created in all animals. This area was wounded and tumor inoculation was performed in both groups.

WOUNDING

Under ether anesthesia, the posterior neck of the mice was cleansed with alcohol (70%). Subcutaneous injection of 5 mL of air created an air sac in the posterior nuchal area of the mice, which was suitable for TI. This area was wounded with the tip of the needle until hemorrhagic fluid was obtained and an erosive wound model was completed.

TUMOR AND PROCEDURE

Weekly intraperitoneal TIs with a line of Ehrlich ascites tumor have been maintained in our animal research laboratory for years. Ascitic fluid of a tumor-bearing animal contains viable and transferable tumor cells, which can establish solid tumor when injected subcutaneously. Tumor cells (8 × 106, calculated in Toma lam [has horizontal and vertical lines forming squares, each of which forms 1 counting field]) were injected into the wounded subcutaneous area in 0.5 mL of isotonic sodium chloride solution.

HISTOPATHOLOGICAL EXAMINATION

The presence of TI was confirmed on the 10th day after inoculation by histopathological examination.

STATISTICAL ANALYSIS

χ2 Test was used for statistical analysis, and P<.05 was considered significant.

A palpable mass (Figure 1), ranging from 0.5 to 3 cm (mean, 1.1 cm) in diameter, was detected in all group 1 mice and was confirmed as TI by histopathological examination (Figure 2). In group 2 mice, no palpable masses were detected but ulcers 0.3 cm in diameter were observed in 3 mice. Histopathological examination of group 2 mice revealed TI in 8 animals. Tumor implantation was verified by histopathological examination in 2 animals with ulcers, whereas examination revealed TI in 6 animals without any macroscopic abnormalities (Figure 3). Application of honey induced inflammatory cell infiltration to the wound cavity while preventing tumor cell invasion (Figure 4 and Figure 5). Tumor implantation was less likely in group 2 mice (8 of 30 vs 30 of 30; P<.001; χ2 = 34.7).

Place holder to copy figure label and caption
Figure 1.

Macroscopic appearance of subcutaneous tumor implantation.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Dense tumor infiltration is easily seen under the derma and dermal appendices in control group mice (hematoxylin-eosin, original magnification ×200).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Tumor implantation in the group with the honey covering, with relatively less dense tumor infiltration (hematoxylin-eosin, original magnification ×200).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Successfully prevented tumor implantation with a protective covering of honey. A tumor-free cavity is seen under the derma and dermal appendices (hematoxylin-eosin, original magnification ×100).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Inflammatory cell invasion is seen in tumor-free mice with topical honey application (hematoxylin-eosin, original magnification ×200).

Graphic Jump Location

Statistical analysis revealed that a protective covering of wounds with honey significantly reduced TI (P<.001).

Liotta and colleagues17,18 proposed a 3-step hypothesis describing the sequence of biochemical events during tumor cell invasion of the extracellular matrix: attachment of the tumor cell, local proteolysis of the basal membrane, and locomotion of the tumor cells within the tissue. A wound barrier that has no deleterious effect on healing may protect the wound against tumor cell invasion by eliminating tumor cell attachment. Results of this study suggest that honey provides a simple, effective, and harmless barrier to TI. Furthermore, honey might inhibit the local proteolysis step by altering the wound's milieu. The hypertonicity of honey itself may also create a destructive environment around the tumor cells that ultimately causes cell shrinking.

Clinical and experimental studies about TI have become popular again after the reports about TSR.211 The mechanism of TSR, which is most likely a form of TI, remains unclear despite numerous studies.28 Exfoliation of tumor cells due to tumor manipulation may lead to TI.11,19 Jones et al3 showed increasing amounts of the deposition of free intraperitoneal viable tumor cells into experimental trocar site wounds as local isolated recurrences. A scintigraphic model confirmed the possible role of exfoliated cells.20 Contributing to the implantation of tumor cells may be pneumoperitoneum, carbon dioxide, increased abdominal pressure, the desufflation rate of pneumoperitoneum, and a chimney effect of carbon dioxide leakage around the trocars.28,19 Wu et al5 demonstrated that local treatment of abdominal wounds with povidone-iodine and silver sulfadiazine reduced TI. However, these agents do not accelerate wound healing, as does honey, and may in fact impair it. Local excision of trocar site wounds has also been shown to reduce TI.8 These factors affirm that local mechanisms may play a role in the formation of TSR. With this knowledge, local protection of wounds with a material that provides an effective barrier against wound invasion may prevent TSR. Presumably, the same principles are applicable to both TSR and TI in subcutaneous wounds. This is because the main factors that promote TI are surgical trauma and wound healing.2123

Honey has been used to accelerate wound healing since ancient times.1214 Except for the presence of some clostridial spores, honey is sterile and highly bactericidal.12,24,25 γ-Irradiation sufficiently sterilizes honey when necessary.24 The wound healing and antimicrobial properties of honey may be attributed to its hypertonicity, low pH, and acceleration of epithelization as well as the presence of inhibin, a thermolabile substance, and enzymes such as catalase.1214,25 Honey also has a hygroscopic effect in reducing edema and constitutes a viscous barrier against wound invasion.12 Honey contains caffeic acid ester derivatives at levels of 20% to 25%.15 These compounds affect a broad spectrum of activities, including possible tumor inhibition.15,16 Topical application of honey on wounds leads to faster eradication of bacterial infections.26 The osmotic effects of honey appear to aid its antibacterial and antitumor activity.27

Ehrlich ascites tumor was first derived from mammary cells of rats.28 Supply maintenance of this tumor is carried out in our research laboratory by weekly intraperitoneal injection in BALB/c mice. Subcutaneous injection of 8 × 106 tumor cells in 0.5 mL of isotonic sodium chloride obtained from ascites of a tumor-bearing animal is adequate to establish solid TI (Figure 1 and Figure 2). Ehrlich ascites tumor, which is highly invasive and transferable, can be used as a TI model in mice. In this study, TI formation was established in all control group animals. The application of honey interrupted TI when used before and after tumor inoculation.

Honey could be used on trocar wounds of patients with malignant disease to prevent TSR. It may also prevent infection with its bactericidal effects. Wound healing may even be enhanced with topical application of honey. Clinical use of honey on trocar wounds is not likely to cause any detrimental effects. Honey may also provide benefit in conventional oncological surgery where TI is predictable. However, metabolic effects of honey when used on large lesions are not known and need further investigation.

In conclusion, preventive covering of surgical wounds with honey seems to be a harmless procedure and may constitute at least a partial barrier that might overcome tumor cell invasion.

We thank Pinar Akan, MD, and Dilek Solakoglu, MD, for their assistance.

Presented at the 8th Biannual Meeting of the Turkish Society of Colon and Rectum Surgeons, September 13, 1999, Kemer-Antalya, Turkey.

Reprints: İsmail Hamzaoglu, MD, Department of Surgery, Cerrahpaşa Medical School, İstanbul University, E-2/3 A-9 34750, 5. Kisim Ataköy, İstanbul, Turkey (e-mail: hulya@turk.net).

Fusco  MAPaluzzi  MW Abdominal wall recurrence after laparoscopic-assisted colectomy for adenocarcinoma of the colon: report of a case. Dis Colon Rectum. 1993;36858- 861
Link to Article
Jacobi  CAOrdemann  JBöhm  B  et al.  The influence of laparotomy and laparoscopy on tumor growth in a rat model. Surg Endosc. 1997;11618- 621
Link to Article
Jones  DBGuo  LWReinhard  MK  et al.  Impact of pneumoperitoneum on trocar site implantation of colon cancer in hamster model. Dis Colon Rectum. 1995;381182- 1188
Link to Article
Mathew  GWatson  DIRofe  AMBaigrie  CFEllis  TJamieson  GG Wound metastases following laparoscopic and open surgery for abdominal cancer in a rat model. Br J Surg. 1996;831087- 1090
Link to Article
Wu  JSPfister  SMRuiz  MBConnett  JMFleshman  JW Local treatment of abdominal wound reduces tumor implantation. J Surg Oncol. 1998;699- 14
Link to Article
Watson  DIMathew  GEllis  TBaigreie  CFRofe  AMJamieson  GG Gasless laparoscopy may reduce the risk of port-site metastases following laparoscopic tumor surgery. Arch Surg. 1997;132166- 168
Link to Article
Wu  JSBrasfield  EBGuo  LW  et al.  Implantation of colon cancer at trocar sites is increased by low pressure pneumoperitoneum. Surgery. 1997;1221- 7
Link to Article
Wu  JSGuo  LWRuiz  MBPfister  SMConnett  JMFleshman  JW Excision of trocar sites reduces tumor implantation in an animal model. Dis Colon Rectum. 1998;411107- 1111
Link to Article
Poulin  ECMamazza  JSchlachta  CMGregoire  RRoy  N Laparoscopic resection does not adversely affect early survival curves in patients undergoing surgery for colorectal adenocarcinoma. Ann Surg. 1999;229487- 492
Link to Article
Bouvet  MMansfield  PFSkibber  JM  et al.  Clinical, pathologic, and economic parameters of laparoscopic colon resection for cancer. Am J Surg. 1998;176554- 558
Link to Article
Ricardo  AEFeig  BWEllis  LM  et al.  Gallbladder cancer and trocar site recurrences. Am J Surg. 1997;174619- 623
Link to Article
Bergmann  AYanai  JWeiss  JBell  DDavid  MP Acceleration of wound healing by topical application of honey. Am J Surg. 1983;145374- 376
Link to Article
Efem  SE Clinical observations on the wound healing properties of honey. Br J Surg. 1988;75679- 681
Link to Article
Subrahmanyam  M Topical application of honey in treatment of burns. Br J Surg. 1991;78497- 498
Link to Article
Rao  CVDesai  DSimi  BKulkarni  NAmin  SReddy  BS Inhibitory effect of caffeic acid esters on azoxymethane-induced biochemical changes and aberrant crypt foci formation in rat colon. Cancer Res. 1993;534182- 4188
Mitamura  TMatsuno  TSakamoto  S  et al.  Effects of a new clerodane diterpenoid isolated from propolis on chemically induced skin tumors in mice. Anticancer Res. 1996;162669- 2672
Liotta  LA Tumor invasion and metastases: role of the basement membrane [Warner-Lambert Parke-Davis award lecture]. Am J Pathol. 1984;117339- 348
Woodhouse  ECChuaqui  RFLiotta  LA General mechanisms of metastasis. Cancer. 1997;801529- 1537
Link to Article
Iwanaka  TArya  GZiegler  MM Mechanism and prevention of port-site tumor recurrence after laparoscopy in a murine model. J Pediatr Surg. 1998;33457- 461
Link to Article
Cavina  EGoletti  OMolea  N  et al.  Trocar site recurrences: may pneumoperitoneum be responsible? Surg Endosc. 1998;121294- 1296
Link to Article
Lee  JYMurphy  SMScanlon  EF Effect of trauma on implantation of metastatic tumor in bone in mice. J Surg Oncol. 1994;56178- 184
Link to Article
Murthy  SMGoldschimidt  RARao  LNAmmirati  MBuchmann  TScanlon  EF The influence of surgical trauma on experimental metastasis. Cancer. 1989;642035- 2044
Link to Article
Hofer  SOMolema  GHermens  RAWanebo  HJReichner  JSHoekstra  HJ The effect of surgical wounding on tumor development. Eur J Surg Oncol. 1999;25231- 243
Link to Article
Molan  PCAllen  KL The effect of γ-irradiation on the antibacterial activity of honey. J Pharm Pharmacol. 1996;481206- 1209
Link to Article
Efem  SE The antimicrobial spectrum of honey and its clinical significance. Infection. 1992;20227- 229
Link to Article
Al-Waili  NSSaloom  KY Effects of topical honey on post-operative wound infections due to gram positive and gram negative bacteria following caesarean sections and hysterectomies. Eur J Med Res. 1999;4126- 130
Osato  MSReddy  SGGraham  DY Osmotic effect of honey on growth and viability of Helicobacter pylori. Dig Dis Sci. 1999;44462- 464
Link to Article
Harveit  FHallereker  B Effect of subcutaneous transplants of Ehrlich carcinoma on the survival time of mice with intraperitoneal transplants of the same tumour. J Pathol. 1971;10585- 93
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Macroscopic appearance of subcutaneous tumor implantation.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Dense tumor infiltration is easily seen under the derma and dermal appendices in control group mice (hematoxylin-eosin, original magnification ×200).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Tumor implantation in the group with the honey covering, with relatively less dense tumor infiltration (hematoxylin-eosin, original magnification ×200).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Successfully prevented tumor implantation with a protective covering of honey. A tumor-free cavity is seen under the derma and dermal appendices (hematoxylin-eosin, original magnification ×100).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Inflammatory cell invasion is seen in tumor-free mice with topical honey application (hematoxylin-eosin, original magnification ×200).

Graphic Jump Location

Tables

References

Fusco  MAPaluzzi  MW Abdominal wall recurrence after laparoscopic-assisted colectomy for adenocarcinoma of the colon: report of a case. Dis Colon Rectum. 1993;36858- 861
Link to Article
Jacobi  CAOrdemann  JBöhm  B  et al.  The influence of laparotomy and laparoscopy on tumor growth in a rat model. Surg Endosc. 1997;11618- 621
Link to Article
Jones  DBGuo  LWReinhard  MK  et al.  Impact of pneumoperitoneum on trocar site implantation of colon cancer in hamster model. Dis Colon Rectum. 1995;381182- 1188
Link to Article
Mathew  GWatson  DIRofe  AMBaigrie  CFEllis  TJamieson  GG Wound metastases following laparoscopic and open surgery for abdominal cancer in a rat model. Br J Surg. 1996;831087- 1090
Link to Article
Wu  JSPfister  SMRuiz  MBConnett  JMFleshman  JW Local treatment of abdominal wound reduces tumor implantation. J Surg Oncol. 1998;699- 14
Link to Article
Watson  DIMathew  GEllis  TBaigreie  CFRofe  AMJamieson  GG Gasless laparoscopy may reduce the risk of port-site metastases following laparoscopic tumor surgery. Arch Surg. 1997;132166- 168
Link to Article
Wu  JSBrasfield  EBGuo  LW  et al.  Implantation of colon cancer at trocar sites is increased by low pressure pneumoperitoneum. Surgery. 1997;1221- 7
Link to Article
Wu  JSGuo  LWRuiz  MBPfister  SMConnett  JMFleshman  JW Excision of trocar sites reduces tumor implantation in an animal model. Dis Colon Rectum. 1998;411107- 1111
Link to Article
Poulin  ECMamazza  JSchlachta  CMGregoire  RRoy  N Laparoscopic resection does not adversely affect early survival curves in patients undergoing surgery for colorectal adenocarcinoma. Ann Surg. 1999;229487- 492
Link to Article
Bouvet  MMansfield  PFSkibber  JM  et al.  Clinical, pathologic, and economic parameters of laparoscopic colon resection for cancer. Am J Surg. 1998;176554- 558
Link to Article
Ricardo  AEFeig  BWEllis  LM  et al.  Gallbladder cancer and trocar site recurrences. Am J Surg. 1997;174619- 623
Link to Article
Bergmann  AYanai  JWeiss  JBell  DDavid  MP Acceleration of wound healing by topical application of honey. Am J Surg. 1983;145374- 376
Link to Article
Efem  SE Clinical observations on the wound healing properties of honey. Br J Surg. 1988;75679- 681
Link to Article
Subrahmanyam  M Topical application of honey in treatment of burns. Br J Surg. 1991;78497- 498
Link to Article
Rao  CVDesai  DSimi  BKulkarni  NAmin  SReddy  BS Inhibitory effect of caffeic acid esters on azoxymethane-induced biochemical changes and aberrant crypt foci formation in rat colon. Cancer Res. 1993;534182- 4188
Mitamura  TMatsuno  TSakamoto  S  et al.  Effects of a new clerodane diterpenoid isolated from propolis on chemically induced skin tumors in mice. Anticancer Res. 1996;162669- 2672
Liotta  LA Tumor invasion and metastases: role of the basement membrane [Warner-Lambert Parke-Davis award lecture]. Am J Pathol. 1984;117339- 348
Woodhouse  ECChuaqui  RFLiotta  LA General mechanisms of metastasis. Cancer. 1997;801529- 1537
Link to Article
Iwanaka  TArya  GZiegler  MM Mechanism and prevention of port-site tumor recurrence after laparoscopy in a murine model. J Pediatr Surg. 1998;33457- 461
Link to Article
Cavina  EGoletti  OMolea  N  et al.  Trocar site recurrences: may pneumoperitoneum be responsible? Surg Endosc. 1998;121294- 1296
Link to Article
Lee  JYMurphy  SMScanlon  EF Effect of trauma on implantation of metastatic tumor in bone in mice. J Surg Oncol. 1994;56178- 184
Link to Article
Murthy  SMGoldschimidt  RARao  LNAmmirati  MBuchmann  TScanlon  EF The influence of surgical trauma on experimental metastasis. Cancer. 1989;642035- 2044
Link to Article
Hofer  SOMolema  GHermens  RAWanebo  HJReichner  JSHoekstra  HJ The effect of surgical wounding on tumor development. Eur J Surg Oncol. 1999;25231- 243
Link to Article
Molan  PCAllen  KL The effect of γ-irradiation on the antibacterial activity of honey. J Pharm Pharmacol. 1996;481206- 1209
Link to Article
Efem  SE The antimicrobial spectrum of honey and its clinical significance. Infection. 1992;20227- 229
Link to Article
Al-Waili  NSSaloom  KY Effects of topical honey on post-operative wound infections due to gram positive and gram negative bacteria following caesarean sections and hysterectomies. Eur J Med Res. 1999;4126- 130
Osato  MSReddy  SGGraham  DY Osmotic effect of honey on growth and viability of Helicobacter pylori. Dig Dis Sci. 1999;44462- 464
Link to Article
Harveit  FHallereker  B Effect of subcutaneous transplants of Ehrlich carcinoma on the survival time of mice with intraperitoneal transplants of the same tumour. J Pathol. 1971;10585- 93
Link to Article

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