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Port Site Metastasis after Surgery for Renal Cell Carcinoma: Harbinger of Future Metastasis Joseph Song,* Eric Kim,* Jonathan Mobley,* Goutham Vemana,* Youssef Tanagho,* Joel Vetter,* Sam Bhayani,† Paul Russo,‡ Oscar Fugita, Stephen Shei-Dei Yang, Masatsugu Iwamura and Robert S. Figenshau§,jj From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri (JS, EK, JM, GV, YT, JV, SB, RSF), Memorial Sloan-Kettering Cancer Center, New York, New York (PR), University of Sao Paulo, Sao Paulo, Brazil (OF), En Chu Kong Hospital, Taipei, Taiwan (SSDY), and Kitasato University, Sagamihara, Japan (MI)
Purpose: Port site metastasis is a rare occurrence after minimally invasive treatment for renal cell carcinoma. However, its prognostic implications are unclear because reports in the literature are heterogeneous in detail and followup. We clarify the significance of port site metastasis in cancer specific survival and broaden our understanding of this phenomenon. Materials and Methods: A MEDLINEÒ search for published studies of renal cell carcinoma port site metastasis was performed. Contributing factors to port site metastasis, stage, Fuhrman grade, pathology, port site metastasis treatment method, followup protocol and long-term outcomes were collected. The corresponding authors of each publication were contacted to fill in details and provide long-term outcomes. We added 1 case from our recent experience. Results: A total of 16 cases from 12 authors (including ourselves) were found. Of the 12 authors 8 were available for correspondence and 9 cases were updated. Eventual outcomes were available for 11 of the 16 cases and survival curves showed poor prognosis with a 31.8% overall 1-year survival rate. Of the 16 cases 12 were radical nephrectomy and 4 were partial nephrectomy, and 13 involved multiple metastases in addition to the port site metastasis. Nine of the cases had no identifiable technical reason for port site metastasis formation such as specimen morcellation, absence of entrapment or tumor rupture. These tumors were uniformly aggressive, Fuhrman grade 3 or higher. Conclusions: Port site metastasis after minimally invasive surgery for renal cell carcinoma is a rare occurrence with a poor prognosis. In most cases port site metastasis is not an isolated metastasis but instead is a harbinger of progressive disease. While technical factors can have a role in port site metastasis formation, it appears that biological factors like high tumor grade also contribute.
Abbreviations and Acronyms PSM ¼ port site metastasis RCC ¼ renal cell carcinoma Accepted for publication February 18, 2014. * Nothing to disclose. † Financial interest and/or other relationship with Intuitive and SurgiQuest. ‡ Financial interest and/or other relationship with Wilex AG. § Correspondence: Campus Box 8242, 4960 Children’s Place, St. Louis, Missouri 63110 (telephone: 314-454-2235; FAX: 314-367-5016; e-mail: [email protected]). k Financial interest and/or other relationship with Amgen and Midwest Stone Institute.
Editor’s Note: This article is the of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages and .
Key Words: neoplasm metastasis; carcinoma, renal cell; laparoscopy; recurrence
MINIMALLY invasive treatment of malignancy has become increasingly common. Laparoscopy is associated with decreased hospitalization times, faster recovery, decreased pain and
improved cosmesis. Port site metastasis is a rare and troubling occurrence in patients after minimally invasive surgical treatment of renal cell carcinoma.
0022-5347/14/1922-0001/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2014.02.089 Vol. 192, 1-5, August 2014 Printed in U.S.A.
www.jurology.com
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POSTOPERATIVE PORT SITE METASTASIS IN RENAL CELL CARCINOMA
In 1978 Dobronte et al first described PSM after diagnostic laparoscopy for ovarian cancer. Since then, PSM has been documented in a range of cancers, including malignancies of the colon, gallbladder, adrenals and urothelium. Certain cancers have a known predilection for PSM. Cancers of the gallbladder have a PSM incidence as high as 14% to 30% and are associated with high rates of peritoneal carcinomatosis.1 However, PSM in gynecologic and colorectal cancers is less common, with rates as high as 4% and 5%, respectively.2,3 In 1994 Stolla et al were the first to report PSM after treatment of urological malignancy when they described a case of subcutaneous PSM of transitional cell carcinoma.4 Subsequently more than 50 cases of urological PSM have been reported.5 However, PSM of renal cell carcinoma remains poorly understood, in part due to the rarity with which it is reported. To date, only 16 cases of RCC PSM have been published. Among these accounts, information regarding PSM treatment and eventual patient outcome is heterogeneous. To better understand the prognostic implications of a PSM we contacted the authors of all published reports of RCC PSM and compiled details regarding these cases.
METHODS An electronic search of the MEDLINE database for all published literature regarding RCC PSM through the year 2013 was performed. “Port site metastasis” and “renal” were entered as keywords for the search, and the 55 results matching these terms were reviewed. Publications which reported a case of RCC PSM were included, and those that represented a duplicate reference to previously published RCC PSM cases were excluded from the study. Overall 13 publications from 12 authors were identified, resulting in 16 cases of PSM after laparoscopic or robotic surgery for RCC. Information regarding the index procedure, tumor stage and pathology, and PSM presentation was compiled. The corresponding authors for these publications were contacted for additional details regarding PSM treatment approach, followup protocol and eventual patient outcome. In cases for which initial contact could not be made, at least 5 attempts during a 2-month period were made to reach the corresponding author.
RESULTS Details of the 16 cases of RCC PSM are summarized in the supplementary table (http://jurology. com/). Of the 12 authors 8 were available for correspondence and their cases were updated. PSM occurred after laparoscopic radical nephrectomy (12), laparoscopic partial nephrectomy (3) and robot-assisted partial nephrectomy (1). Seven cases had identifiable causes for PSM, including specimen morcellation (3), lack of entrapment during Dochead: Adult Urology
172 tumor extraction (2) and tumor rupture (2). Nine 173 cases identified no technical impetus for PSM for174 mation. Index tumor pathology included clear cell 175 (11), papillary (4) and chromophobe RCC (1). Mean 176 time to PSM presentation was 16 months (range 177 3 to 39, median 11). Initial PSM presentation 178 varied, including isolated port site metastasis (6), 179 multiple port sites (3) and widespread disease (7). 180 Of the 9 patients who presented with isolated PSM 181 more widespread disease eventually developed in 6. 182 One patient presenting with widespread metas183 tases died of pulmonary embolism before PSM 184 treatment could be initiated. Otherwise, surgical 185 resection of the PSM was the primary treatment 186 modality in 56% of cases (9 of 16), comprised of 187 1 laparoscopic and 8 open approaches. 188 Among the 9 patients who presented with only 189 PSM and no other metastatic disease, 7 underwent 190 surgical tumor excision. Of the 2 patients who did 191 not undergo this treatment 1 with an isolated PSM 192 received radiation, and another with multiple port 193 site metastases received chemotherapy and radia194 tion. Among the 7 patients who presented with 195 widespread disease surgical resection was less 196 common, with 2 undergoing surgical resection of 197 PSM and other metastases. Of the 5 patients who 198 did not undergo surgical resection 1 received suni199 tinib plus radiation, another died before treatment 200 could be initiated and 3 did not have primary 201 treatment information available. The primary 202 author of these 3 cases did not respond to our re203 quests for updated information. 204 Mean followup was 29 months after PSM treat205 ment (median 12, range 0.5 to 86) after updated 206 author responses. Survival outcome was unavail207 able for 5 cases for which survival was not reported 208 in the original manuscript or followup correspon209 dence. However, 4 of these patients presented with 210 widely metastatic disease at PSM diagnosis. Of the 211 11 other cases with survival data available the 212 overall 1-year probability of survival after PSM treatment was 31.8% (see figure). ½F1 213 214 The cancer specific probability of survival after 215 PSM treatment was 35% at 1 year (see figure). Five 216 patients with metastasis did not die of their disease, 217 whereas 1 patient with widespread metastasis died 218 of pulmonary embolism 17 days after PSM treat219 ment. Another patient with stable lung metastases 220 died of congestive heart failure 86 months after 221 PSM treatment. Three patients with metastatic 222 disease were still alive at 10, 12 and 72 months, 223 respectively. 224 225 226 DISCUSSION 227 The number of reports concerning PSM and the true 228 incidence of PSM are not known. Large series on
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Probability of survival following PSM treatment
PSM formation after laparoscopic oncologic procedures have reported an incidence of approximately 0.5% to 2%, comparable to the 0.8% to 1.6% rate of wound implantation reported in open procedures.6e8 While there is a dearth of information on wound implantation after open nephrectomy or partial nephrectomy, multiple reports for colorectal cancers place the risk of cutaneous incision metastasis at approximately 1%, similar to the rate reported for laparoscopic RCC.9 Furthermore, animal models have shown no difference in cutaneous occurrence rates after open vs laparoscopic surgery.10,11 While randomized and prospective trials have been stymied by the rarity of this phenomenon, available data do suggest that PSM and wound implantation after open surgery have similar rates of occurrence. In the cases of RCC PSM identified here it is clear that PSM remains a troubling occurrence associated with a poor prognosis. Many theories have been proposed to explain this phenomenon, including use of pneumoperitoneum, physical violation of the tumor, trocar site contamination, specimen morcellation and use of an entrapment bag during specimen retrieval.5 Lack of tumor isolation and use of morcellation during specimen removal have been suggested as major factors in PSM formation. However, only 2 cases out of the 16 occurrences of PSM identified did not use an entrapment bag.12,13 In both of these cases metastasis occurred to the port used for extraction. Of the 16 cases 3 involved specimen Dochead: Adult Urology
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morcellation before extraction,14e16 which has been shown to increase the risk of pinhole perforations in entrapment bags.17 Whether the type of entrapment bag used has a role in the occurrence of PSM is unknown. While certain bags such as LAPSACÒ have been shown to better maintain impermeability after morcellation,17 whether this advantage carries over to cases without morcellation is unclear. Only Fentie et al used a LAPSAC but the relevance of its use is uncertain.14 Ultimately morcellation of tumor should be avoided regardless of the entrapment bag used as this greatly increases the risk of tumor seeding. In addition to the extraction method, violation of tumor has also been put forth as a factor in PSM formation. Masterson and Russo highlighted a fragmented tumor as a likely key contributor to RCC PSM in their 2008 case report.18 Shortly afterward Greco et al reported a case of RCC PSM after specimen rupture.19 In both cases gross tumor spillage was thought to have led to implantation of tumor cells. Although it is clear that factors related to surgical technique contribute to PSM, 9 of the 16 cases of RCC PSM identified in our search had no identifiable cause of PSM formation. While this does not eliminate the issue of technique related factors in PSM, it raises the issue of nontechnical reasons for PSM. One possible reason for PSM formation might be factors intrinsic to laparoscopic surgery. Mathew et al found that the use of gas insufflation significantly increased the risk of PSM compared to gasless laparoscopy.20 According to the authors of this and similar studies, pneumoperitoneum contributes to PSM by causing a chimney effect due to leakage of gas which carries viable tumor cells from the abdomen to the area of gas leak. In addition, the use of CO2 itself might contribute to PSM formation by stimulating tumor growth and inhibiting local defense factors.21 However, gas insufflation alone is unlikely to have a major role in PSM formation. Wittich et al demonstrated that the escape of gas is unable to deposit enough cells to lead to tumor growth and concluded that gas leak was not a major factor in PSM pathogenesis.22 Furthermore, in all these studies significant amounts of viable tumor cells had to be seeded to the abdomen. Thus, it is difficult for this model to account for PSM, which occurs without major violation of the tumor. Recently the biological factors which contribute to tumor formation have been increasingly emphasized. Chaturvedi et al identified 4 instances of RCC PSM which they attributed to circulating tumor cells.23 In all cases entrapment was used, morcellation was avoided and tumor was not violated. However, all 4 of these cases had metastasis to both
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port sites as well as to distant organs, suggesting that the patients already had advanced disease which had spread beyond the kidney. Chuang et al also concluded that tumor and not operative factors are responsible for PSM formation.24 Similarly, in our earlier report of PSM after robot-assisted partial nephrectomy, no surgeon related factors were identified and PSM occurred at a camera port site not used for specimen extraction.25 Initially we believed metastatic disease was limited to the port site. However, the patient presented with multiple intrahepatic, renal and peritoneal metastases 6 months after resection of the original tumor. Indeed, among all 16 cases of PSM, 13 experienced eventual distant metastasis. When examining only the 9 cases in which we found no identifiable technique related causes for PSM, 7 had metastasis to nonport locations. The other 2 cases had limited followup and were not available for correspondence. While not conclusive, this finding supports the notion that PSM can form as a result of aggressive circulating tumor cells, which will likely lead to multiple metastases. Further evidence for this theory comes from the nature of the primary tumor reported in most cases of PSM. Of the 16 cases of PSM 12 had information available on Fuhrman grade. Among these 12 cases 9 had a grade of 3 or higher. The remaining 3 cases were all Fuhrman grade 2, and involved technique related factors which could have contributed to PSM as 1 case did not use entrapment and the other 2 used morcellation. Thus, in those cases for which no surgical factors could be identified, the tumors were uniformly high grade, supporting the notion that PSM is a result of an aggressive primary tumor likely to metastasize to multiple distant sites. Aside from aggressive tumor biology, other factors might predispose port sites to being conducive to circulating tumor cells. As previously mentioned, CO2 has been shown to hasten tumor growth. In addition, local wound factors have been known to aid the implantation of tumor cells and increase the risk of tumor cell deposition by as much as 1,000fold.26 This drastic increase is attributed to several factors. Collagen deposition during healing can provide a surface on which tumor cells can adhere. Indeed, murine models have shown that collagen promotes tumor growth resulting from circulating cancer cells.27 In addition, growth factors and angiogenesis occurring naturally at the incision site could further promote tumor proliferation.28 As a result, port sites represent an ideal location for circulating tumor cells to deposit and proliferate. Indeed, PSM may be an early indicator of metastasis to other locations. Dochead: Adult Urology
Among the 9 patients who presented with only PSM, metastasis to other sites eventually developed in 6. This number could be even higher as 2 of the 3 reports of isolated PSM without distant metastasis had limited followup and 4 cases with distant metastasis other than PSM did not report the order in which tumors were identified. While our data are incomplete as we were unable to contact all authors of reported PSM, the available literature supports a theory that PSM is a poor prognostic factor and is rarely an isolated event. Instead, when PSM occurs without identifiable technique related factors in the index surgery, it is common for multiple metastases to eventually develop. These conclusions have also been suggested in the gynecologic literature. Zivanovic et al found high rates of synchronous metastasis in ovarian cancer and concluded that PSM is a surrogate for advanced disease.29 Whether this phenomenon is specific to laparoscopic surgery is uncertain. While wound metastases are observed with similar frequencies in open surgery,11e16 we did not identify any publications which investigated long-term outcomes after open wound implantation. Perhaps because of the high risk of distant metastasis, our study shows that patients with PSM have a poor prognosis. Among the 11 patients for whom we were able to obtain survival data the overall probability of survival at 1 year was 31.8%, comparable to an approximately 50% 1-year survival for metastatic RCC reported in the literature.30 While our sample size was small, this finding strongly suggests that the occurrence of PSM indicates poor prognosis.
CONCLUSIONS PSM after laparoscopic surgery is a rare occurrence. While technical factors can have a role in PSM, long-term followup of the known cases of RCC PSM strongly suggests that factors outside of surgeon control, such as tumor biology and processes inherent to laparoscopy, are a significant cause of PSM formation. The majority of PSM cases are accompanied by eventual development of other metastatic disease, suggesting the presence of circulating tumor cells. Thus, PSM is often a harbinger of progressive disease, with 1-year survival rates comparable to or worse than those of widely metastatic disease.
ACKNOWLEDGMENTS Dr. Larry Taranger, Dr. Octavio Castillo and Dr. Francesco Greco provided correspondence without which this study could not have been possible.
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REFERENCES 1. Yildirim S, Ezer A, Colakoglu T et al: An unusual case of port site metastasis after laparoscopic cholecystectomy in a renal transplant patient: a case report. Transplant Proc 2006; 38: 1369. 2. Nagarsheth NP, Rahaman J, Cohen CJ et al: The incidence of port-site metastases in gynecologic cancers. JSLS 2004; 8: 133. 3. Paolucci V, Schaeff B, Schneider M et al: Tumor seeding following laparoscopy: international survey. World J Surg 1999; 23: 989. 4. Stolla V, Rossi D, Bladou F et al: Subcutaneous metastases after coelioscopic lymphadenectomy for vesical urothelial carcinoma. Eur Urol 1994; 26: 342. 5. Kadi N, Isherwood M, Al-Akraa M et al: Portsite metastasis after laparoscopic surgery for urological malignancy: forgotten or missed. Adv Urol 2012; 2012: 609531. 6. Micali S, Celia A, Bove P et al: Tumor seeding in urological laparoscopy: an international survey. J Urol 2004; 171: 2151. 7. Rassweiler J, Tsivian A, Kumar AV et al: Oncological safety of laparoscopic surgery for urological malignancy: experience with more than 1,000 operations. J Urol 2003; 169: 2072. 8. Reilly WT, Nelson H, Schroeder G et al: Wound recurrence following conventional treatment of colorectal cancer. A rare but perhaps underestimated problem. Dis Colon Rectum 1996; 39: 200. 9. Allardyce RA: Is the port site really at risk? Biology, mechanisms and prevention: a critical view. Aust N Z J Surg 1999; 69: 479. 10. Paik PS, Misawa T, Chiang M et al: Abdominal incision tumor implantation following pneumoperitoneum laparoscopic procedure vs. standard open incision in a syngeneic rat model. Dis Colon Rectum 1998; 41: 419. 11. Hofstetter W, Ortega A, Chiang M et al: Abdominal insufflation does not cause
Dochead: Adult Urology
hematogenous spread of colon cancer. J Laparoendosc Adv Surg Tech A 2000; 10: 1. 12. Chen YT, Yang SS, Hsieh CH et al: Hand port-site metastasis of renal-cell carcinoma following hand-assisted laparoscopic radical nephrectomy: case report. J Endourol 2003; 17: 771. 13. Iwamura M, Tsumura H, Matsuda D et al: Port site recurrence of renal cell carcinoma following retroperitoneoscopic radical nephrectomy with manual extraction without using entrapment sac or wound protector. J Urol 2004; 171: 1234. 14. Fentie DD, Barrett PH and Taranger LA: Metastatic renal cell cancer after laparoscopic radical nephrectomy: long-term follow-up. J Endourol 2000; 14: 407. 15. Castilho LN, Fugita OE, Mitre AI et al: Port site tumor recurrences of renal cell carcinoma after videolaparoscopic radical nephrectomy. J Urol 2001; 165: 519. 16. Landman J and Clayman RV: Re: Port site tumor recurrences of renal cell carcinoma after videolaparoscopic radical nephrectomy. J Urol 2001; 166: 629. 17. Urban DA, Kerbl K, McDougall EM et al: Organ entrapment and renal morcellation: permeability studies. J Urol 1993; 150: 1792. 18. Masterson TA and Russo P: A case of port-site recurrence and locoregional metastasis after laparoscopic partial nephrectomy. Nat Clin Pract Urol 2008; 5: 345. 19. Greco F, Wagner S, Reichelt O et al: Huge isolated port-site recurrence after laparoscopic partial nephrectomy: a case report. Eur Urol 2009; 56: 737. 20. Mathew G, Watson DI, Ellis T et al: The effect of laparoscopy on the movement of tumor cells and metastasis to surgical wounds. Surg Endosc 1997; 11: 1163. 21. Kuntz C, Wunsch A, B€odeker C et al: Effect of pressure and gas type on intraabdominal,
subcutaneous, and blood pH in laparoscopy. Surg Endosc 2000; 14: 367. 22. Wittich P, Marquet RL, Kazemier G et al: Portsite metastases after CO(2) laparoscopy. Is aerosolization of tumor cells a pivotal factor? Surg Endosc 2000; 14: 189. 23. Chaturvedi S, Bansal V, Kapoor R et al: Is port site metastasis a result of systemic involvement? Indian J Urol 2012; 28: 169. 24. Chuang XE, Loh HL, Sim HG et al: Papillary renal cell carcinoma with metastatic laparoscopic port site and vaginal involvement: a case report. J Med Case Rep 2011; 5: 131. 25. Song JB, Tanagho YS, Kim EH et al: Camera-port site metastasis of a renal-cell carcinoma after robot-assisted partial nephrectomy. J Endourol 2013; 27: 732. 26. Skipper D, Jeffrey MJ, Cooper AJ et al: Enhanced growth of tumour cells in healing colonic anastomoses and laparotomy wounds. Int J Colorectal Dis 1989; 4: 172. 27. Reinbach D, McGregor JR, Dahill SW et al: Collagen promotes perianastomotic tumour growth in an experimental animal model. J Surg Oncol 1995; 60: 112. 28. Murthy SM, Goldschmidt RA, Rao LN et al: The influence of surgical trauma on experimental metastasis. Cancer 1989; 64: 2035. 29. Zivanovic O, Sonoda Y, Diaz JP et al: The rate of port-site metastases after 2251 laparoscopic procedures in women with underlying malignant disease. Gynecol Oncol 2008; 111: 431. 30. Pal SK, Nelson RA and Vogelzang N: Diseasespecific survival in de novo metastatic renal cell carcinoma in the cytokine and targeted therapy era. PLoS One 2013; 8: e63341.
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Port Site Metastasis after Surgery for Renal Cell Carcinoma: Harbinger of Future Metastasis Joseph Song,* Eric Kim,* Jonathan Mobley,* Goutham Vemana,* Youssef Tanagho,* Joel Vetter,* Sam Bhayani,† Paul Russo,‡ Oscar Fugita, Stephen Shei-Dei Yang, Masatsugu Iwamura and Robert S. Figenshau§,jj From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri (JS, EK, JM, GV, YT, JV, SB, RSF), Memorial Sloan-Kettering Cancer Center, New York, New York (PR), University of Sao Paulo, Sao Paulo, Brazil (OF), En Chu Kong Hospital, Taipei, Taiwan (SSDY), and Kitasato University, Sagamihara, Japan (MI)
Purpose: Port site metastasis is a rare occurrence after minimally invasive treatment for renal cell carcinoma. However, its prognostic implications are unclear because reports in the literature are heterogeneous in detail and followup. We clarify the significance of port site metastasis in cancer specific survival and broaden our understanding of this phenomenon. Materials and Methods: A MEDLINEÒ search for published studies of renal cell carcinoma port site metastasis was performed. Contributing factors to port site metastasis, stage, Fuhrman grade, pathology, port site metastasis treatment method, followup protocol and long-term outcomes were collected. The corresponding authors of each publication were contacted to fill in details and provide long-term outcomes. We added 1 case from our recent experience. Results: A total of 16 cases from 12 authors (including ourselves) were found. Of the 12 authors 8 were available for correspondence and 9 cases were updated. Eventual outcomes were available for 11 of the 16 cases and survival curves showed poor prognosis with a 31.8% overall 1-year survival rate. Of the 16 cases 12 were radical nephrectomy and 4 were partial nephrectomy, and 13 involved multiple metastases in addition to the port site metastasis. Nine of the cases had no identifiable technical reason for port site metastasis formation such as specimen morcellation, absence of entrapment or tumor rupture. These tumors were uniformly aggressive, Fuhrman grade 3 or higher. Conclusions: Port site metastasis after minimally invasive surgery for renal cell carcinoma is a rare occurrence with a poor prognosis. In most cases port site metastasis is not an isolated metastasis but instead is a harbinger of progressive disease. While technical factors can have a role in port site metastasis formation, it appears that biological factors like high tumor grade also contribute.
Abbreviations and Acronyms PSM ¼ port site metastasis RCC ¼ renal cell carcinoma Accepted for publication February 18, 2014. * Nothing to disclose. † Financial interest and/or other relationship with Intuitive and SurgiQuest. ‡ Financial interest and/or other relationship with Wilex AG. § Correspondence: Campus Box 8242, 4960 Children’s Place, St. Louis, Missouri 63110 (telephone: 314-454-2235; FAX: 314-367-5016; e-mail: [email protected]). k Financial interest and/or other relationship with Amgen and Midwest Stone Institute.
Editor’s Note: This article is the of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages and .
Key Words: neoplasm metastasis; carcinoma, renal cell; laparoscopy; recurrence
MINIMALLY invasive treatment of malignancy has become increasingly common. Laparoscopy is associated with decreased hospitalization times, faster recovery, decreased pain and
improved cosmesis. Port site metastasis is a rare and troubling occurrence in patients after minimally invasive surgical treatment of renal cell carcinoma.
0022-5347/14/1922-0001/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2014.02.089 Vol. 192, 1-5, August 2014 Printed in U.S.A.
www.jurology.com
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In 1978 Dobronte et al first described PSM after diagnostic laparoscopy for ovarian cancer. Since then, PSM has been documented in a range of cancers, including malignancies of the colon, gallbladder, adrenals and urothelium. Certain cancers have a known predilection for PSM. Cancers of the gallbladder have a PSM incidence as high as 14% to 30% and are associated with high rates of peritoneal carcinomatosis.1 However, PSM in gynecologic and colorectal cancers is less common, with rates as high as 4% and 5%, respectively.2,3 In 1994 Stolla et al were the first to report PSM after treatment of urological malignancy when they described a case of subcutaneous PSM of transitional cell carcinoma.4 Subsequently more than 50 cases of urological PSM have been reported.5 However, PSM of renal cell carcinoma remains poorly understood, in part due to the rarity with which it is reported. To date, only 16 cases of RCC PSM have been published. Among these accounts, information regarding PSM treatment and eventual patient outcome is heterogeneous. To better understand the prognostic implications of a PSM we contacted the authors of all published reports of RCC PSM and compiled details regarding these cases.
METHODS An electronic search of the MEDLINE database for all published literature regarding RCC PSM through the year 2013 was performed. “Port site metastasis” and “renal” were entered as keywords for the search, and the 55 results matching these terms were reviewed. Publications which reported a case of RCC PSM were included, and those that represented a duplicate reference to previously published RCC PSM cases were excluded from the study. Overall 13 publications from 12 authors were identified, resulting in 16 cases of PSM after laparoscopic or robotic surgery for RCC. Information regarding the index procedure, tumor stage and pathology, and PSM presentation was compiled. The corresponding authors for these publications were contacted for additional details regarding PSM treatment approach, followup protocol and eventual patient outcome. In cases for which initial contact could not be made, at least 5 attempts during a 2-month period were made to reach the corresponding author.
RESULTS Details of the 16 cases of RCC PSM are summarized in the supplementary table (http://jurology. com/). Of the 12 authors 8 were available for correspondence and their cases were updated. PSM occurred after laparoscopic radical nephrectomy (12), laparoscopic partial nephrectomy (3) and robot-assisted partial nephrectomy (1). Seven cases had identifiable causes for PSM, including specimen morcellation (3), lack of entrapment during Dochead: Adult Urology
172 tumor extraction (2) and tumor rupture (2). Nine 173 cases identified no technical impetus for PSM for174 mation. Index tumor pathology included clear cell 175 (11), papillary (4) and chromophobe RCC (1). Mean 176 time to PSM presentation was 16 months (range 177 3 to 39, median 11). Initial PSM presentation 178 varied, including isolated port site metastasis (6), 179 multiple port sites (3) and widespread disease (7). 180 Of the 9 patients who presented with isolated PSM 181 more widespread disease eventually developed in 6. 182 One patient presenting with widespread metas183 tases died of pulmonary embolism before PSM 184 treatment could be initiated. Otherwise, surgical 185 resection of the PSM was the primary treatment 186 modality in 56% of cases (9 of 16), comprised of 187 1 laparoscopic and 8 open approaches. 188 Among the 9 patients who presented with only 189 PSM and no other metastatic disease, 7 underwent 190 surgical tumor excision. Of the 2 patients who did 191 not undergo this treatment 1 with an isolated PSM 192 received radiation, and another with multiple port 193 site metastases received chemotherapy and radia194 tion. Among the 7 patients who presented with 195 widespread disease surgical resection was less 196 common, with 2 undergoing surgical resection of 197 PSM and other metastases. Of the 5 patients who 198 did not undergo surgical resection 1 received suni199 tinib plus radiation, another died before treatment 200 could be initiated and 3 did not have primary 201 treatment information available. The primary 202 author of these 3 cases did not respond to our re203 quests for updated information. 204 Mean followup was 29 months after PSM treat205 ment (median 12, range 0.5 to 86) after updated 206 author responses. Survival outcome was unavail207 able for 5 cases for which survival was not reported 208 in the original manuscript or followup correspon209 dence. However, 4 of these patients presented with 210 widely metastatic disease at PSM diagnosis. Of the 211 11 other cases with survival data available the 212 overall 1-year probability of survival after PSM treatment was 31.8% (see figure). ½F1 213 214 The cancer specific probability of survival after 215 PSM treatment was 35% at 1 year (see figure). Five 216 patients with metastasis did not die of their disease, 217 whereas 1 patient with widespread metastasis died 218 of pulmonary embolism 17 days after PSM treat219 ment. Another patient with stable lung metastases 220 died of congestive heart failure 86 months after 221 PSM treatment. Three patients with metastatic 222 disease were still alive at 10, 12 and 72 months, 223 respectively. 224 225 226 DISCUSSION 227 The number of reports concerning PSM and the true 228 incidence of PSM are not known. Large series on
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PSM formation after laparoscopic oncologic procedures have reported an incidence of approximately 0.5% to 2%, comparable to the 0.8% to 1.6% rate of wound implantation reported in open procedures.6e8 While there is a dearth of information on wound implantation after open nephrectomy or partial nephrectomy, multiple reports for colorectal cancers place the risk of cutaneous incision metastasis at approximately 1%, similar to the rate reported for laparoscopic RCC.9 Furthermore, animal models have shown no difference in cutaneous occurrence rates after open vs laparoscopic surgery.10,11 While randomized and prospective trials have been stymied by the rarity of this phenomenon, available data do suggest that PSM and wound implantation after open surgery have similar rates of occurrence. In the cases of RCC PSM identified here it is clear that PSM remains a troubling occurrence associated with a poor prognosis. Many theories have been proposed to explain this phenomenon, including use of pneumoperitoneum, physical violation of the tumor, trocar site contamination, specimen morcellation and use of an entrapment bag during specimen retrieval.5 Lack of tumor isolation and use of morcellation during specimen removal have been suggested as major factors in PSM formation. However, only 2 cases out of the 16 occurrences of PSM identified did not use an entrapment bag.12,13 In both of these cases metastasis occurred to the port used for extraction. Of the 16 cases 3 involved specimen Dochead: Adult Urology
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morcellation before extraction,14e16 which has been shown to increase the risk of pinhole perforations in entrapment bags.17 Whether the type of entrapment bag used has a role in the occurrence of PSM is unknown. While certain bags such as LAPSACÒ have been shown to better maintain impermeability after morcellation,17 whether this advantage carries over to cases without morcellation is unclear. Only Fentie et al used a LAPSAC but the relevance of its use is uncertain.14 Ultimately morcellation of tumor should be avoided regardless of the entrapment bag used as this greatly increases the risk of tumor seeding. In addition to the extraction method, violation of tumor has also been put forth as a factor in PSM formation. Masterson and Russo highlighted a fragmented tumor as a likely key contributor to RCC PSM in their 2008 case report.18 Shortly afterward Greco et al reported a case of RCC PSM after specimen rupture.19 In both cases gross tumor spillage was thought to have led to implantation of tumor cells. Although it is clear that factors related to surgical technique contribute to PSM, 9 of the 16 cases of RCC PSM identified in our search had no identifiable cause of PSM formation. While this does not eliminate the issue of technique related factors in PSM, it raises the issue of nontechnical reasons for PSM. One possible reason for PSM formation might be factors intrinsic to laparoscopic surgery. Mathew et al found that the use of gas insufflation significantly increased the risk of PSM compared to gasless laparoscopy.20 According to the authors of this and similar studies, pneumoperitoneum contributes to PSM by causing a chimney effect due to leakage of gas which carries viable tumor cells from the abdomen to the area of gas leak. In addition, the use of CO2 itself might contribute to PSM formation by stimulating tumor growth and inhibiting local defense factors.21 However, gas insufflation alone is unlikely to have a major role in PSM formation. Wittich et al demonstrated that the escape of gas is unable to deposit enough cells to lead to tumor growth and concluded that gas leak was not a major factor in PSM pathogenesis.22 Furthermore, in all these studies significant amounts of viable tumor cells had to be seeded to the abdomen. Thus, it is difficult for this model to account for PSM, which occurs without major violation of the tumor. Recently the biological factors which contribute to tumor formation have been increasingly emphasized. Chaturvedi et al identified 4 instances of RCC PSM which they attributed to circulating tumor cells.23 In all cases entrapment was used, morcellation was avoided and tumor was not violated. However, all 4 of these cases had metastasis to both
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port sites as well as to distant organs, suggesting that the patients already had advanced disease which had spread beyond the kidney. Chuang et al also concluded that tumor and not operative factors are responsible for PSM formation.24 Similarly, in our earlier report of PSM after robot-assisted partial nephrectomy, no surgeon related factors were identified and PSM occurred at a camera port site not used for specimen extraction.25 Initially we believed metastatic disease was limited to the port site. However, the patient presented with multiple intrahepatic, renal and peritoneal metastases 6 months after resection of the original tumor. Indeed, among all 16 cases of PSM, 13 experienced eventual distant metastasis. When examining only the 9 cases in which we found no identifiable technique related causes for PSM, 7 had metastasis to nonport locations. The other 2 cases had limited followup and were not available for correspondence. While not conclusive, this finding supports the notion that PSM can form as a result of aggressive circulating tumor cells, which will likely lead to multiple metastases. Further evidence for this theory comes from the nature of the primary tumor reported in most cases of PSM. Of the 16 cases of PSM 12 had information available on Fuhrman grade. Among these 12 cases 9 had a grade of 3 or higher. The remaining 3 cases were all Fuhrman grade 2, and involved technique related factors which could have contributed to PSM as 1 case did not use entrapment and the other 2 used morcellation. Thus, in those cases for which no surgical factors could be identified, the tumors were uniformly high grade, supporting the notion that PSM is a result of an aggressive primary tumor likely to metastasize to multiple distant sites. Aside from aggressive tumor biology, other factors might predispose port sites to being conducive to circulating tumor cells. As previously mentioned, CO2 has been shown to hasten tumor growth. In addition, local wound factors have been known to aid the implantation of tumor cells and increase the risk of tumor cell deposition by as much as 1,000fold.26 This drastic increase is attributed to several factors. Collagen deposition during healing can provide a surface on which tumor cells can adhere. Indeed, murine models have shown that collagen promotes tumor growth resulting from circulating cancer cells.27 In addition, growth factors and angiogenesis occurring naturally at the incision site could further promote tumor proliferation.28 As a result, port sites represent an ideal location for circulating tumor cells to deposit and proliferate. Indeed, PSM may be an early indicator of metastasis to other locations. Dochead: Adult Urology
Among the 9 patients who presented with only PSM, metastasis to other sites eventually developed in 6. This number could be even higher as 2 of the 3 reports of isolated PSM without distant metastasis had limited followup and 4 cases with distant metastasis other than PSM did not report the order in which tumors were identified. While our data are incomplete as we were unable to contact all authors of reported PSM, the available literature supports a theory that PSM is a poor prognostic factor and is rarely an isolated event. Instead, when PSM occurs without identifiable technique related factors in the index surgery, it is common for multiple metastases to eventually develop. These conclusions have also been suggested in the gynecologic literature. Zivanovic et al found high rates of synchronous metastasis in ovarian cancer and concluded that PSM is a surrogate for advanced disease.29 Whether this phenomenon is specific to laparoscopic surgery is uncertain. While wound metastases are observed with similar frequencies in open surgery,11e16 we did not identify any publications which investigated long-term outcomes after open wound implantation. Perhaps because of the high risk of distant metastasis, our study shows that patients with PSM have a poor prognosis. Among the 11 patients for whom we were able to obtain survival data the overall probability of survival at 1 year was 31.8%, comparable to an approximately 50% 1-year survival for metastatic RCC reported in the literature.30 While our sample size was small, this finding strongly suggests that the occurrence of PSM indicates poor prognosis.
CONCLUSIONS PSM after laparoscopic surgery is a rare occurrence. While technical factors can have a role in PSM, long-term followup of the known cases of RCC PSM strongly suggests that factors outside of surgeon control, such as tumor biology and processes inherent to laparoscopy, are a significant cause of PSM formation. The majority of PSM cases are accompanied by eventual development of other metastatic disease, suggesting the presence of circulating tumor cells. Thus, PSM is often a harbinger of progressive disease, with 1-year survival rates comparable to or worse than those of widely metastatic disease.
ACKNOWLEDGMENTS Dr. Larry Taranger, Dr. Octavio Castillo and Dr. Francesco Greco provided correspondence without which this study could not have been possible.
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