- Email: [email protected]
Wilms' tumour with persistent intravascular extension: A review of the surgical aspects of management
Journal of Pediatric Urology (2006) 2, 439e445
Wilms’ tumour with persistent intravascular extension: A review of the surgical aspects of management G.V. Murthi a,*, E. Kocyildirim b, S. Sellathury a, P.M. Cuckow a, D.T. Wilcox a, A. Michalski c, N.J. Sebire d, M.J. Elliott b, P.G. Duffy a a
Department of Paediatric Urology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK b Department of Cardio-Thoracic Surgery, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK c Department of Haemato-Oncology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK d Department of Pathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK Received 12 July 2005; accepted 4 October 2005 Available online 1 December 2005
KEYWORDS Wilms’ tumour; Surgery; Persistent Intravascular extension; Cardiopulmonary bypass
Abstract Aim: To review the surgical management of Wilms’ tumour with persistent intravascular (vena caval þ/ atrial) tumour extension. Patients and methods: Data were collected regarding operative details, tumour and ‘thrombus’ histology, and long-term outcome for patients with Wilms’ tumour with cavo-artial extension. Result: From 1988 to 2004, 13 patients underwent treatment for Wilms’ tumour with persistent intravascular extension. Preoperative chemotherapy was administered in 11/13 patients and postoperative radiotherapy in eight patients. Intravascular involvement was upto IVC (5), and right atrium (8) patients. Techniques employed for excision of intra-vascular component were: local cavotomy (3), extensive infra-diaphragmatic cavotomy without cardiopulmonary bypass (CPB) (1), and excision of cavo-atrial tumour with CPB (þ/ hypothermia and cardiac arrest) (9). Mean time on CPB was 90 min. Caval repair was accomplished by primary repair (6) and pericardial graft in (7) patients. There were no intraoperative deaths and few major complications. Tumour thrombus contained malignant cells in 10/13 cases. Mean follow up has been for 55.4 months. To date, seven patients remain disease-free (one lost to
* Corresponding author. Tel.: þ44 116 2718814; fax: þ44 115 9709006. E-mail address: [email protected] (G.V. Murthi). 1477-5131/$30 ª 2005 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2005.10.004
440
G.V. Murthi et al. follow up), disease recurred in five patients, three of whom have died. There were no symptoms related to the graft. Conclusions: Surgery for Wilms’ tumour with persistent intravascular extension despite chemotherapy is technically challenging. CPB þ/ hypothermia and cardiac arrest and extensive caval repair with a graft is safe and reliable in the long term. ª 2005 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction The prognosis for children with Wilms’ tumour has improved dramatically over the last few decades, largely as a result of coordinated trials (NWTS I-V, SIOP, UKCCSG) and the introduction of multi-modal therapy. Wilms’ tumour with intravascular extension of tumour thrombus into the inferior vena cava (4e10%) [1,2] and further on into the right atrium (0.7%) [3] remains a therapeutic challenge. The demonstration of an increased incidence of surgical complications following primary nephrectomy in this group of patients [3,4] has led to the use of preoperative chemotherapy. Preoperative chemotherapy has been reported to cause tumour shrinkage [2,5e7], which facilitates surgical excision. In some patients, tumour thrombus persists despite preoperative chemotherapy and represents a formidable technical challenge, especially if there is supra-hepatic or intra-atrial extension. In this situation, cardiopulmonary bypass (CPB), deep hypothermia with circulatory arrest (DHCA) or without circulatory arrest, anti-coagulation, and extensive repair of the vena cava following thrombus excision are required. This complex surgical approach has been associated with severe morbidity [8,9]. We review our experience of the management of children with Wilms’ tumour and persistent intravascular tumour thrombus despite preoperative chemotherapy. The surgical aspects of management of persistent intravascular extension of tumour thrombus are discussed.
Methods With the approval of the Local Research Ethics Committee, the records of all children undergoing surgery from 1988 to 2004 for Wilms’ tumour with persistent cavalþ/atrial tumour thrombus were reviewed with regard to their surgical management, histology of tumour and thrombus, and long-term outcome. Multi-drug preoperative chemotherapy in accordance with current UKCCSG protocol was administered in order to diminish
the extent of intravascular tumour involvement and facilitate surgery. Imaging methods used to delineate the extent of intravascular thrombus have varied over the years and a combination of US, CT (Fig. 1), MRI and echocardiography have been used. During the course of chemotherapy, the response of the primary tumour and the accompanying thrombus was closely monitored. The timing of surgery was determined by the response to chemotherapy, the extent of thrombus, and the volume and appearance of thrombus within the right atrium on imaging. Decisions were made following multi-disciplinary consultations including an oncologist, urologist and cardiac surgeon. The surgical approach consists of two components. The renal tumour is approached via a rooftop or transverse upper abdominal incision. Careful mobilization of the entire tumour is undertaken outside Gerota’s fascia. Then, the renal pedicle is dissected to clearly identify the renal artery and vein and their insertion into the aorta and inferior vena cava (IVC), respectively. Ipsilateral adrenal vessels also need careful dissection, followed by division of the renal artery and the ureter between ligatures. Subsequently, the extent of surgery and the need for CPB is determined by the extent of intravascular thrombus. Infra-diaphragmatic thrombus is removed following isolation of the IVC and contralateral renal vessels on vascular slings and opening it longitudinally, i.e. cavotomy. Care is taken to apply the slings beyond the limits of thrombus in order to avoid embolization during extraction. Supra-hepatic or atrial involvement necessitated a median sternotomy extended inferiorly to the abdominal wound in the midline as a ‘t’ or ‘inverted-Y’. The diaphragm is divided anteriorly in the midline and the liver rotated anteromedially to expose the entire length of the IVC to the heart. After systemic heparinization, the ascending aorta, right atrium and superior vena cava are cannulated (size 14e16 F cannula). The right femoral vein or IVC is then cannulated (size 6 F cannula). The pulmonary artery is immediately snared to prevent tumour embolus going to the lung. Moderate-to-deep hypothermia with or
Wilms’ tumour with persistent intravascular extension
441
thrombus extirpation. Primary repair of the IVC with Prolene suture is accomplished if possible. Usually, however, following extensive dissection, the application of a bovine pericardial graft is best as it enables restoration of adequate IVC calibre. After haemostasis is secured and hypothermia reversed, cardiac arrest and bypass are discontinued. The incisions are closed after the placement of pericardial and pleural drains, these being removed 24e48 h later. Histological examination of the tumour and thrombus was performed. Patients continued further chemotherapyþ/radiotherapy as dictated by disease staging. The cardiologist reviews in the long term all patients that underwent cardiac bypass surgery and have grafts in situ for IVC repair. Aspirin is prescribed for long-term anticoagulation for patients with grafts but compliance is unreliable.
Results
Figure 1 (A) Contrast-enhanced CT of the abdomen demonstrating that the inferior vena cava is expanded by intravascular tumour, with only a small residual lumen (arrows). (B) Contrast-enhanced CT of the abdomen demonstrating that the inferior vena cava (arrow) is expanded by intravascular tumour.
without cardiac arrest and aortic cross-clamping is used to facilitate surgery and reduce postoperative morbidity. Trasylol (aprotonin injection), a broad-spectrum protease inhibitor, was used in some cases to reduce the need for blood transfusion. The IVC is then incised longitudinally along its entire length, and a circumferential incision around the involved renal vein allows visualization of the tumour thrombus extending from the kidney into the IVC. Thrombectomy is achieved by a combination of digital and blunt instrumental dissection. As the thrombus is often densely adherent to the endothelium of the IVC it cannot always be removed intact up to its extension into the atrium (Fig. 2). Extension inferiorly and into the opposite renal vein (Fig. 3) is not uncommon and requires further careful dissection and
From 1988 to 2004, 13 children (six males and seven females) underwent surgery for Wilms’ tumour with intravascular extension. Wilms’ tumour involved the right kidney in 12 patients and one patient had bilateral involvement with thrombus extension arising from the more extensive right-side tumour. Mean age at presentation was 56 months (range 31e108 months). None of the children presented with symptoms attributable to cavo-atrial invasion by thrombus. Pre-therapy imaging detected the intravascular involvement in 12 of 13 patients. The level of pre-therapy extension was the IVC in four and atrium in eight patients.
Figure 2 Photograph of resected atrial Wilms’ tumour, with frond-like areas to the left that represent organizing non-tumour thrombus that has developed distal to the tumour growth.
442
G.V. Murthi et al. underwent further postoperative chemotherapy in accordance with the UKCCSG protocol for the stage of disease. Following the same protocols, eight of 13 patients also underwent postoperative radiotherapy.
Surgical techniques
Figure 3 Photograph of resected right Wilms’ tumour with a large tumour thrombus extending into the iliac bifurcation and into the opposite renal vein.
Chemotherapy and radiotherapy Eleven of 13 patients received triple drug (vincristine, actinomycin, doxorubicin) preoperative chemotherapy as per UKCCSG protocol for a mean period of 10 weeks (range 1e29 weeks) in an attempt to diminish the extent of tumour involvement. Chemotherapy was not administered preoperatively in one patient considered for primary nephrectomy, the intravascular extension only being detected intraoperatively. In a second child, the intra-atrial thrombus appeared to be on a very narrow pedicle upon echocardiography and primary surgical excision was undertaken to avoid the potential risk of tumour detachment and fatal embolism following initiation of chemotherapy. Similarly, another child received only 1 week of preoperative chemotherapy before this was abandoned in favour of surgical excision because of a massive intra-atrial thrombus that showed no response to chemotherapy. Intravascular extension diminished from the atrium into the IVC in only three of eight patients (37.5%) following preoperative chemotherapy as detected by post-chemotherapy imaging, and this was corroborated by findings at surgery. All patients
In addition to nephrectomy (all patients) the surgical techniques employed for excision of the intravascular component included: local cavotomy (3), extensive infra-diaphragmatic cavotomy without CPB (1), and excision of cavo-atrial tumour with CPB support (deep hypothermia and cardiac arrest) (9). Details of surgery under CPB in these nine patients are shown in Table 1. Excision of the intravascular component was macroscopically complete in all but one patient. In this patient, the caval component of the tumour in the abdomen was considered inoperable and planned CPB was abandoned. Subsequently, excision of a massive intraatrial component of the tumour was undertaken on CPB to prevent a potentially fatal embolism. Mean time on CPB was 90 min (range 58e 127 min). Blood loss could not be estimated due to use of the bypass pump. Restoration of vena caval lumen was accomplished by primary repair with 6/0 prolene suture in five patients. Bovine pericardial grafts (Supple Peri-guard, Bio-Vascular, Inc., St Paul, MN, USA) were used to repair extensive post-extirpation defects in the IVC in six patients and in one patient an autologous pericardial graft was used. A short video of the operative procedure can be viewed at http:// www.congenitalheartsurgery.net There was no instance of tumour breakage or distal embolism. There were no intraoperative deaths. There was no evidence of postoperative renal insufficiency as monitored by plasma creatinine levels. There were no neurological complications from the use of CPB and DHCA. Complications included pleural effusion (n ¼ 2), pericardial effusion (n ¼ 1), gross hematuria (n ¼ 1) and ileus (n ¼ 2).
Histology Histological examination of the excised renal tumour showed Wilms’ tumour (n ¼ 11), clear cell sarcoma (n ¼ 1) and primitive neuro-ectodermal tumour (n ¼ 1). Histology of the excised tumour thrombus showed persistent viable tumour in 10/ 13 specimens. No viable tumour was visible in three patients, all having received chemotherapy. In other words, viable tumour was present in the thrombus despite chemotherapy in 8/11 patients.
Wilms’ tumour with persistent intravascular extension
443
Table 1 Details of operative procedures in nine patients who underwent extirpation of tumour under cardiopulmonary bypass (CPB)
1 2 3 4 5 6 7 8 9
CPB (min)
Aortic cross-clamping (min)
Circulatory arrest (min)
Hypothermia ( C)
Cold blood cardioplegia
Trasylol (ml)
IVC repair
84 126 84 127 58 123 144 69 198
No No 16 57 No No No No No
No No 8 28 No No No No No
17 32 18 15 30 25 24 22 18
No No Yes Yes Yes Yes No No No
No 50 No 14 No 20 13 No No
Autologous graft Primary repair Primary repair Bovine graft Bovine graft Bovine graft Bovine graft Bovine graft Bovine graft
Mortality Mean follow up has been for 55.4 months (range 6e 120 months). To date, seven patients remain disease-free (one patient has emigrated and is lost to follow up) and five patients have had recurrence of disease. Three of these five patients have died from severe intra-thoracic disease unresponsive to intensive therapy. In the remaining two patients, recurrence has occurred in the lungs and in the renal fossa in one patient each and they are under treatment. There has been no recurrence of tumour in the inferior vena caval or atrial lumen. There have been no symptoms related to the graft.
Discussion Survival rates for children with Wilms’ tumours, especially with the development of additional chemotherapeutic regimens and the use of radiation therapy, have improved dramatically and approach 90% for even the most advanced stages of disease. Wilms’ tumour with intravascular extension, occurring in 4.1% and 6.0% of NWTS-3 and NWTS-4, respectively, continues to present a surgical challenge. Apart from one large series from NWTS-4 [10] and a report from the SIOP/GPOH study [9], most reports in the literature dealing with this subset of Wilms’ tumour patients consist of a small series of case reports. Few deal with the technical aspects of the surgical approach in children [11]. The risk of an increased incidence of surgical complications [3,4] and the benefits of preoperative chemotherapy in this situation [2,5e7] are well documented; prognosis for longterm survival, however, does not appear to be worsened [1]. The aim of the surgical therapy is the radical removal of neoplastic tissue, including the
thrombus in the IVC and the involved caval wall, as well as caval wall reconstruction. If extensive exposure and isolation of the IVC is required, CPB with or without deep hypothermic circulatory arrest can be used. The extent of the surgical approach is determined by the extent of intravascular involvement. We pursue an aggressive approach to the management of patients with chemo-resistant vena caval extension of their tumour, in the absence of extensive metastatic disease. For infra-hepatic caval thrombus, providing proximal and distal vascular control is achieved, CPB can be avoided and primary repair of the IVC is feasible. Retro-hepatic and more distal extension into the atrium requires CPB and we used it for all nine cases where this situation existed. Average time on CPB was 90 min (range 58e127 min). As an institutional approach, systemic heparin administration and CPB is our treatment of choice. DHCA is employed whenever blood flow to the brain has to be interrupted or a bloodless cardiac surgical field is required, e.g. IVC repair. Clinical deep hypothermia is defined as a nasopharyngeal temperature below 20 C. The advantage is reduced oxygen consumption, especially of the brain (O2 consumption decreases by 50% for every 10 C drop in body temperature). Circulatory arrest is when the entire cardiac output is drained out of the body into the CPB machine pump and the pump is switched off. The extremely low temperature allows surgical repairs to be undertaken without any severe adverse effects, e.g. ischaemia, and cerebrovascular effects leading to neurological effects of stroke, cerebral oedema and neurodevelopmental defects in the paediatric group. Coagulopathy is also a major problem. Once repair is completed, the patient is gradually re-warmed and blood flow is gently re-established into the circulation. There is no major difference in the
444 technique between adults and children. There are no studies comparing the relative effects of the duration of DHCA between adults and children and a ‘safe’ duration for DHCA remains undefined [12]. Whilst there is perhaps an increased concern for the ‘safe’ duration of circulatory arrest time in children, two separate studies assessing the neurological outcomes following administration of DHCA in children [12] and adults [13] have arrived at a similar time period of less than 40 min as being associated with reduced morbidity. Although recent reports advocate the routine use of DHCA in adults for removal of tumour thrombus in the vena cava [14], its use in children with Wilms’ tumour is extremely uncommon and usually confined to case reports [15e17]. We prefer to avoid DHCA because of its known neurological dangers [12], and we have found that most patients can be managed without it. DHCA is considered for those patients in whom adequate visualization of the tumour cannot be achieved without it (patients 1, 3, 4 and 9 in Table 1). Aortic cross-clamping was also used in two of these (patients 3 and 4 in Table 1) patients only. The circulatory arrest time was 8 and 28 min for these two patients, well below the ‘safe’ duration of less than 40 min observed in the study by Wypij et al. [12]. Ritchey et al. [4], in their review of children in NWTS-3 who underwent primary nephrectomy, found a higher rate of surgical complications in patients with intravascular extension with an odds ratio of 2.2. A subsequent report by the same first author [8] reviewing a later study (NWTS-4) found a much reduced incidence of surgical complications, although children with intravascular extension of tumour still remained at a higher risk than the others. This improvement in reduced morbidity is reflected in other recent studies [2,9,10,15] and is attributed to the use of improved imaging methods in diagnosis, the use of preoperative chemotherapy for tumour shrinkage, and a multi-disciplinary surgical approach including the appropriate and planned use of CPB and DHCA. These observations are reflected in the results from the current series in which there were no intraoperative deaths and postoperative morbidity was minimal. Long-term morbidity and mortality in patients with intravascular extension appears to be influenced neither by the presence of intravascular disease nor by its extent [1]. In the largest reported series of patients treated for this condition (165 patients), Shamberger et al. [10] found no adverse effect on the 3-year relapse-free survival rate when compared with that of 1621 patients without intravascular extension, when considered in aggregate, by stage or by pathologic subgroup. Relapse
G.V. Murthi et al. and death in our group of patients has not been due to recurrence in the intravascular compartment. In fact, to date, there has been no recurrence of tumour in the intravascular compartment in any patient. The presence of viable tumour cells in the excised tumour thrombus upon histological examination, despite preoperative chemotherapy, as seen in 8/11 (72.7%) of our patients, does not appear to be detrimental with regard to local recurrence in the vascular compartment. Similarly, Shamberger et al. [10] have reported no increased incidence of relapse in 18 patients with incomplete removal of tumour thrombus. This information possibly indicates that achieving ‘gross clearance’ is preferable to heroic attempts at extensive clearance of caval and atrial lumen of all tumour thrombus at the cost of jeopardizing the subsequent satisfactory repair of the IVC and prolonging time spent on CPB and DHCA, and is safe in the long term. There appear to be no long-term detrimental effects from the insertion of a bovine graft for extensive IVC repair. Although we advocate the use of aspirin as an anti-thrombotic measure, information on patient compliance in this regard is lacking. This and the documentation of graft patency will be the subject of a future study. Any possible consequences from thrombotic occlusion of the caval neo-lumen are perhaps obviated by the development of adequate retroperitoneal collaterals in these children. In conclusion, although the treatment of Wilms’ tumour with persistent cavo-atrial tumour thrombus remains a surgical challenge, aggressive treatment is warranted. The use of pre- and postoperative chemotherapy, a multidisciplinary approach to surgical decision making with close cooperation between oncologist, paediatric urologist and cardio-thoracic surgeons, and the use of radiotherapy has improved the outcome for these children. Our experience suggests that a combined abdomino-thoracic approach by the urologist and cardiac surgeon, with judicious use of CPB and DHCA, allows optimal surgical excision, and satisfactory restoration of inferior vena caval lumen with a bovine pericardial patch graft offers the most benefit for both immediate and long-term outcome measures.
Acknowledgements We wish to thank Dr D. Roebuck, Consultant Interventional Radiologist, for contributing the CT images (Fig. 1A and B) that were used in this manuscript.
Wilms’ tumour with persistent intravascular extension
References [1] Ritchey ML, Kelalis PP, Breslow N, Offord KP, Shochat SJ, D’Angio GJ. Intracaval and atrial involvement with nephroblastoma: review of National Wilms Tumor Study-3. J Urol 1988;140:1113e8. [2] Akyuz C, Emir S, Buyukpamukcu N, Atahan L, Caglar M, Kutluk T, et al. Cavoatrial tumor extension in children with Wilms tumor: a retrospective review of 17 children in a single center. Pediatr Hematol Oncol 2005;27:267e9. [3] Nakayama DK, Norkool P, deLorimier AA, O’Neill Jr JA, D’Angio GJ. Intracardiac extension of Wilms’ tumor. A report of the National Wilms’ Tumor Study. Ann Surg 1986; 204:693e7. [4] Ritchey ML, Kelalis PP, Breslow N, Etzioni R, Evans I, Haase GM, et al. Surgical complications after nephrectomy for Wilms’ tumor. Surg Gynecol Obstet 1992;175:507e14. [5] Kogan SJ, Marans H, Santorineau M, Schneider K, Reda E, Levitt SB. Successful treatment of renal vein and vena caval extension of nephroblastoma by preoperative chemotherapy. J Urol 1986;136:312e7. [6] Crombleholme TM, Jacir NN, Rosenfield CG, Lew S, Harris BH. Preoperative chemotherapy in the management of intracaval extension of Wilms’ tumor. J Pediatr Surg 1994;29:229e31. [7] Oberholzer HF, Falkson G, De Jager LC. Successful management of inferior vena cava and right atrial nephroblastoma tumor thrombus with preoperative chemotherapy. Med Pediatr Oncol 1992;20:61e3. [8] Ritchey ML, Shamberger RC, Haase G, Horwitz J, Bergemann T, Breslow NE. Surgical complications after primary nephrectomy for Wilms’ tumor: report from the National Wilms’ Tumor Study Group. J Am Coll Surg 200;192:63e8.
445
[9] Szavay P, Luithle T, Semler O, Graf N, Fuchs J. Surgery of cavoatrial tumor thrombus in nephroblastoma: a report of the SIOP/GPOH study. Pediatr Blood Cancer 2004;43: 40e5. [10] Shamberger RC, Ritchey ML, Haase GM, Bergemann TL, Loechelt-Yoshioka T, Breslow NE, et al. Intravascular extension of Wilms tumor. Ann Surg 2001;234:116e21. [11] Lodge AJ, Jaggers J, Adams D, Rice HE. Vascular control for resection of suprahepatic intracaval Wilms’ tumour: technical considerations. J Pediatr Surg 2000;35:1836e7. [12] Wypij D, Newburger JW, Rappaport LA, duPlessis AJ, Jonas RA, Wernovsky G, et al. The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003;126:1397e403. [13] Svensson LG, Crawford ES, Hess KR, Coselli JS, Raskin S, Shenaq SA, et al. Deep hypothermia with circulatory arrest. Determinants of stroke and early mortality in 656 patients. J Thorac Cardiovasc Surg 1993;106:19e31. [14] Chiappini B, Savini C, Marinelli G, Suarez SM, Di Eusanio M, Fiorani V, et al. Cavoatrial tumor thrombus: single-stage surgical approach with profound hypothermia and circulatory arrest, including a review of the literature. J Thorac Cardiovasc Surg 2002;124:684e8. [15] Schettini ST, da Fonseca JH, Abib SC, Telles CA, Haber MX, Rizzo MF, et al. Management of Wilms’ tumor with intracardiac extension. Pediatr Surg Int 2000;16:529e32. [16] Sripathi V, Muralidharan KV, Ramesh S, Muralinath S. Wilms’ tumor with vena caval, atrial, and middle hepatic vein tumor thrombus. Pediatr Surg Int 2000;16:447e8. [17] Pannek J, Goepel M, Kremens B, Otto T, Sadony V. Surgical management of Wilms tumor with intracardiac neoplastic extension. Thorac Cardiovasc Surg 1994;42:108e11.
Wilms’ tumour with persistent intravascular extension: A review of the surgical aspects of management G.V. Murthi a,*, E. Kocyildirim b, S. Sellathury a, P.M. Cuckow a, D.T. Wilcox a, A. Michalski c, N.J. Sebire d, M.J. Elliott b, P.G. Duffy a a
Department of Paediatric Urology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK b Department of Cardio-Thoracic Surgery, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK c Department of Haemato-Oncology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK d Department of Pathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK Received 12 July 2005; accepted 4 October 2005 Available online 1 December 2005
KEYWORDS Wilms’ tumour; Surgery; Persistent Intravascular extension; Cardiopulmonary bypass
Abstract Aim: To review the surgical management of Wilms’ tumour with persistent intravascular (vena caval þ/ atrial) tumour extension. Patients and methods: Data were collected regarding operative details, tumour and ‘thrombus’ histology, and long-term outcome for patients with Wilms’ tumour with cavo-artial extension. Result: From 1988 to 2004, 13 patients underwent treatment for Wilms’ tumour with persistent intravascular extension. Preoperative chemotherapy was administered in 11/13 patients and postoperative radiotherapy in eight patients. Intravascular involvement was upto IVC (5), and right atrium (8) patients. Techniques employed for excision of intra-vascular component were: local cavotomy (3), extensive infra-diaphragmatic cavotomy without cardiopulmonary bypass (CPB) (1), and excision of cavo-atrial tumour with CPB (þ/ hypothermia and cardiac arrest) (9). Mean time on CPB was 90 min. Caval repair was accomplished by primary repair (6) and pericardial graft in (7) patients. There were no intraoperative deaths and few major complications. Tumour thrombus contained malignant cells in 10/13 cases. Mean follow up has been for 55.4 months. To date, seven patients remain disease-free (one lost to
* Corresponding author. Tel.: þ44 116 2718814; fax: þ44 115 9709006. E-mail address: [email protected] (G.V. Murthi). 1477-5131/$30 ª 2005 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2005.10.004
440
G.V. Murthi et al. follow up), disease recurred in five patients, three of whom have died. There were no symptoms related to the graft. Conclusions: Surgery for Wilms’ tumour with persistent intravascular extension despite chemotherapy is technically challenging. CPB þ/ hypothermia and cardiac arrest and extensive caval repair with a graft is safe and reliable in the long term. ª 2005 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction The prognosis for children with Wilms’ tumour has improved dramatically over the last few decades, largely as a result of coordinated trials (NWTS I-V, SIOP, UKCCSG) and the introduction of multi-modal therapy. Wilms’ tumour with intravascular extension of tumour thrombus into the inferior vena cava (4e10%) [1,2] and further on into the right atrium (0.7%) [3] remains a therapeutic challenge. The demonstration of an increased incidence of surgical complications following primary nephrectomy in this group of patients [3,4] has led to the use of preoperative chemotherapy. Preoperative chemotherapy has been reported to cause tumour shrinkage [2,5e7], which facilitates surgical excision. In some patients, tumour thrombus persists despite preoperative chemotherapy and represents a formidable technical challenge, especially if there is supra-hepatic or intra-atrial extension. In this situation, cardiopulmonary bypass (CPB), deep hypothermia with circulatory arrest (DHCA) or without circulatory arrest, anti-coagulation, and extensive repair of the vena cava following thrombus excision are required. This complex surgical approach has been associated with severe morbidity [8,9]. We review our experience of the management of children with Wilms’ tumour and persistent intravascular tumour thrombus despite preoperative chemotherapy. The surgical aspects of management of persistent intravascular extension of tumour thrombus are discussed.
Methods With the approval of the Local Research Ethics Committee, the records of all children undergoing surgery from 1988 to 2004 for Wilms’ tumour with persistent cavalþ/atrial tumour thrombus were reviewed with regard to their surgical management, histology of tumour and thrombus, and long-term outcome. Multi-drug preoperative chemotherapy in accordance with current UKCCSG protocol was administered in order to diminish
the extent of intravascular tumour involvement and facilitate surgery. Imaging methods used to delineate the extent of intravascular thrombus have varied over the years and a combination of US, CT (Fig. 1), MRI and echocardiography have been used. During the course of chemotherapy, the response of the primary tumour and the accompanying thrombus was closely monitored. The timing of surgery was determined by the response to chemotherapy, the extent of thrombus, and the volume and appearance of thrombus within the right atrium on imaging. Decisions were made following multi-disciplinary consultations including an oncologist, urologist and cardiac surgeon. The surgical approach consists of two components. The renal tumour is approached via a rooftop or transverse upper abdominal incision. Careful mobilization of the entire tumour is undertaken outside Gerota’s fascia. Then, the renal pedicle is dissected to clearly identify the renal artery and vein and their insertion into the aorta and inferior vena cava (IVC), respectively. Ipsilateral adrenal vessels also need careful dissection, followed by division of the renal artery and the ureter between ligatures. Subsequently, the extent of surgery and the need for CPB is determined by the extent of intravascular thrombus. Infra-diaphragmatic thrombus is removed following isolation of the IVC and contralateral renal vessels on vascular slings and opening it longitudinally, i.e. cavotomy. Care is taken to apply the slings beyond the limits of thrombus in order to avoid embolization during extraction. Supra-hepatic or atrial involvement necessitated a median sternotomy extended inferiorly to the abdominal wound in the midline as a ‘t’ or ‘inverted-Y’. The diaphragm is divided anteriorly in the midline and the liver rotated anteromedially to expose the entire length of the IVC to the heart. After systemic heparinization, the ascending aorta, right atrium and superior vena cava are cannulated (size 14e16 F cannula). The right femoral vein or IVC is then cannulated (size 6 F cannula). The pulmonary artery is immediately snared to prevent tumour embolus going to the lung. Moderate-to-deep hypothermia with or
Wilms’ tumour with persistent intravascular extension
441
thrombus extirpation. Primary repair of the IVC with Prolene suture is accomplished if possible. Usually, however, following extensive dissection, the application of a bovine pericardial graft is best as it enables restoration of adequate IVC calibre. After haemostasis is secured and hypothermia reversed, cardiac arrest and bypass are discontinued. The incisions are closed after the placement of pericardial and pleural drains, these being removed 24e48 h later. Histological examination of the tumour and thrombus was performed. Patients continued further chemotherapyþ/radiotherapy as dictated by disease staging. The cardiologist reviews in the long term all patients that underwent cardiac bypass surgery and have grafts in situ for IVC repair. Aspirin is prescribed for long-term anticoagulation for patients with grafts but compliance is unreliable.
Results
Figure 1 (A) Contrast-enhanced CT of the abdomen demonstrating that the inferior vena cava is expanded by intravascular tumour, with only a small residual lumen (arrows). (B) Contrast-enhanced CT of the abdomen demonstrating that the inferior vena cava (arrow) is expanded by intravascular tumour.
without cardiac arrest and aortic cross-clamping is used to facilitate surgery and reduce postoperative morbidity. Trasylol (aprotonin injection), a broad-spectrum protease inhibitor, was used in some cases to reduce the need for blood transfusion. The IVC is then incised longitudinally along its entire length, and a circumferential incision around the involved renal vein allows visualization of the tumour thrombus extending from the kidney into the IVC. Thrombectomy is achieved by a combination of digital and blunt instrumental dissection. As the thrombus is often densely adherent to the endothelium of the IVC it cannot always be removed intact up to its extension into the atrium (Fig. 2). Extension inferiorly and into the opposite renal vein (Fig. 3) is not uncommon and requires further careful dissection and
From 1988 to 2004, 13 children (six males and seven females) underwent surgery for Wilms’ tumour with intravascular extension. Wilms’ tumour involved the right kidney in 12 patients and one patient had bilateral involvement with thrombus extension arising from the more extensive right-side tumour. Mean age at presentation was 56 months (range 31e108 months). None of the children presented with symptoms attributable to cavo-atrial invasion by thrombus. Pre-therapy imaging detected the intravascular involvement in 12 of 13 patients. The level of pre-therapy extension was the IVC in four and atrium in eight patients.
Figure 2 Photograph of resected atrial Wilms’ tumour, with frond-like areas to the left that represent organizing non-tumour thrombus that has developed distal to the tumour growth.
442
G.V. Murthi et al. underwent further postoperative chemotherapy in accordance with the UKCCSG protocol for the stage of disease. Following the same protocols, eight of 13 patients also underwent postoperative radiotherapy.
Surgical techniques
Figure 3 Photograph of resected right Wilms’ tumour with a large tumour thrombus extending into the iliac bifurcation and into the opposite renal vein.
Chemotherapy and radiotherapy Eleven of 13 patients received triple drug (vincristine, actinomycin, doxorubicin) preoperative chemotherapy as per UKCCSG protocol for a mean period of 10 weeks (range 1e29 weeks) in an attempt to diminish the extent of tumour involvement. Chemotherapy was not administered preoperatively in one patient considered for primary nephrectomy, the intravascular extension only being detected intraoperatively. In a second child, the intra-atrial thrombus appeared to be on a very narrow pedicle upon echocardiography and primary surgical excision was undertaken to avoid the potential risk of tumour detachment and fatal embolism following initiation of chemotherapy. Similarly, another child received only 1 week of preoperative chemotherapy before this was abandoned in favour of surgical excision because of a massive intra-atrial thrombus that showed no response to chemotherapy. Intravascular extension diminished from the atrium into the IVC in only three of eight patients (37.5%) following preoperative chemotherapy as detected by post-chemotherapy imaging, and this was corroborated by findings at surgery. All patients
In addition to nephrectomy (all patients) the surgical techniques employed for excision of the intravascular component included: local cavotomy (3), extensive infra-diaphragmatic cavotomy without CPB (1), and excision of cavo-atrial tumour with CPB support (deep hypothermia and cardiac arrest) (9). Details of surgery under CPB in these nine patients are shown in Table 1. Excision of the intravascular component was macroscopically complete in all but one patient. In this patient, the caval component of the tumour in the abdomen was considered inoperable and planned CPB was abandoned. Subsequently, excision of a massive intraatrial component of the tumour was undertaken on CPB to prevent a potentially fatal embolism. Mean time on CPB was 90 min (range 58e 127 min). Blood loss could not be estimated due to use of the bypass pump. Restoration of vena caval lumen was accomplished by primary repair with 6/0 prolene suture in five patients. Bovine pericardial grafts (Supple Peri-guard, Bio-Vascular, Inc., St Paul, MN, USA) were used to repair extensive post-extirpation defects in the IVC in six patients and in one patient an autologous pericardial graft was used. A short video of the operative procedure can be viewed at http:// www.congenitalheartsurgery.net There was no instance of tumour breakage or distal embolism. There were no intraoperative deaths. There was no evidence of postoperative renal insufficiency as monitored by plasma creatinine levels. There were no neurological complications from the use of CPB and DHCA. Complications included pleural effusion (n ¼ 2), pericardial effusion (n ¼ 1), gross hematuria (n ¼ 1) and ileus (n ¼ 2).
Histology Histological examination of the excised renal tumour showed Wilms’ tumour (n ¼ 11), clear cell sarcoma (n ¼ 1) and primitive neuro-ectodermal tumour (n ¼ 1). Histology of the excised tumour thrombus showed persistent viable tumour in 10/ 13 specimens. No viable tumour was visible in three patients, all having received chemotherapy. In other words, viable tumour was present in the thrombus despite chemotherapy in 8/11 patients.
Wilms’ tumour with persistent intravascular extension
443
Table 1 Details of operative procedures in nine patients who underwent extirpation of tumour under cardiopulmonary bypass (CPB)
1 2 3 4 5 6 7 8 9
CPB (min)
Aortic cross-clamping (min)
Circulatory arrest (min)
Hypothermia ( C)
Cold blood cardioplegia
Trasylol (ml)
IVC repair
84 126 84 127 58 123 144 69 198
No No 16 57 No No No No No
No No 8 28 No No No No No
17 32 18 15 30 25 24 22 18
No No Yes Yes Yes Yes No No No
No 50 No 14 No 20 13 No No
Autologous graft Primary repair Primary repair Bovine graft Bovine graft Bovine graft Bovine graft Bovine graft Bovine graft
Mortality Mean follow up has been for 55.4 months (range 6e 120 months). To date, seven patients remain disease-free (one patient has emigrated and is lost to follow up) and five patients have had recurrence of disease. Three of these five patients have died from severe intra-thoracic disease unresponsive to intensive therapy. In the remaining two patients, recurrence has occurred in the lungs and in the renal fossa in one patient each and they are under treatment. There has been no recurrence of tumour in the inferior vena caval or atrial lumen. There have been no symptoms related to the graft.
Discussion Survival rates for children with Wilms’ tumours, especially with the development of additional chemotherapeutic regimens and the use of radiation therapy, have improved dramatically and approach 90% for even the most advanced stages of disease. Wilms’ tumour with intravascular extension, occurring in 4.1% and 6.0% of NWTS-3 and NWTS-4, respectively, continues to present a surgical challenge. Apart from one large series from NWTS-4 [10] and a report from the SIOP/GPOH study [9], most reports in the literature dealing with this subset of Wilms’ tumour patients consist of a small series of case reports. Few deal with the technical aspects of the surgical approach in children [11]. The risk of an increased incidence of surgical complications [3,4] and the benefits of preoperative chemotherapy in this situation [2,5e7] are well documented; prognosis for longterm survival, however, does not appear to be worsened [1]. The aim of the surgical therapy is the radical removal of neoplastic tissue, including the
thrombus in the IVC and the involved caval wall, as well as caval wall reconstruction. If extensive exposure and isolation of the IVC is required, CPB with or without deep hypothermic circulatory arrest can be used. The extent of the surgical approach is determined by the extent of intravascular involvement. We pursue an aggressive approach to the management of patients with chemo-resistant vena caval extension of their tumour, in the absence of extensive metastatic disease. For infra-hepatic caval thrombus, providing proximal and distal vascular control is achieved, CPB can be avoided and primary repair of the IVC is feasible. Retro-hepatic and more distal extension into the atrium requires CPB and we used it for all nine cases where this situation existed. Average time on CPB was 90 min (range 58e127 min). As an institutional approach, systemic heparin administration and CPB is our treatment of choice. DHCA is employed whenever blood flow to the brain has to be interrupted or a bloodless cardiac surgical field is required, e.g. IVC repair. Clinical deep hypothermia is defined as a nasopharyngeal temperature below 20 C. The advantage is reduced oxygen consumption, especially of the brain (O2 consumption decreases by 50% for every 10 C drop in body temperature). Circulatory arrest is when the entire cardiac output is drained out of the body into the CPB machine pump and the pump is switched off. The extremely low temperature allows surgical repairs to be undertaken without any severe adverse effects, e.g. ischaemia, and cerebrovascular effects leading to neurological effects of stroke, cerebral oedema and neurodevelopmental defects in the paediatric group. Coagulopathy is also a major problem. Once repair is completed, the patient is gradually re-warmed and blood flow is gently re-established into the circulation. There is no major difference in the
444 technique between adults and children. There are no studies comparing the relative effects of the duration of DHCA between adults and children and a ‘safe’ duration for DHCA remains undefined [12]. Whilst there is perhaps an increased concern for the ‘safe’ duration of circulatory arrest time in children, two separate studies assessing the neurological outcomes following administration of DHCA in children [12] and adults [13] have arrived at a similar time period of less than 40 min as being associated with reduced morbidity. Although recent reports advocate the routine use of DHCA in adults for removal of tumour thrombus in the vena cava [14], its use in children with Wilms’ tumour is extremely uncommon and usually confined to case reports [15e17]. We prefer to avoid DHCA because of its known neurological dangers [12], and we have found that most patients can be managed without it. DHCA is considered for those patients in whom adequate visualization of the tumour cannot be achieved without it (patients 1, 3, 4 and 9 in Table 1). Aortic cross-clamping was also used in two of these (patients 3 and 4 in Table 1) patients only. The circulatory arrest time was 8 and 28 min for these two patients, well below the ‘safe’ duration of less than 40 min observed in the study by Wypij et al. [12]. Ritchey et al. [4], in their review of children in NWTS-3 who underwent primary nephrectomy, found a higher rate of surgical complications in patients with intravascular extension with an odds ratio of 2.2. A subsequent report by the same first author [8] reviewing a later study (NWTS-4) found a much reduced incidence of surgical complications, although children with intravascular extension of tumour still remained at a higher risk than the others. This improvement in reduced morbidity is reflected in other recent studies [2,9,10,15] and is attributed to the use of improved imaging methods in diagnosis, the use of preoperative chemotherapy for tumour shrinkage, and a multi-disciplinary surgical approach including the appropriate and planned use of CPB and DHCA. These observations are reflected in the results from the current series in which there were no intraoperative deaths and postoperative morbidity was minimal. Long-term morbidity and mortality in patients with intravascular extension appears to be influenced neither by the presence of intravascular disease nor by its extent [1]. In the largest reported series of patients treated for this condition (165 patients), Shamberger et al. [10] found no adverse effect on the 3-year relapse-free survival rate when compared with that of 1621 patients without intravascular extension, when considered in aggregate, by stage or by pathologic subgroup. Relapse
G.V. Murthi et al. and death in our group of patients has not been due to recurrence in the intravascular compartment. In fact, to date, there has been no recurrence of tumour in the intravascular compartment in any patient. The presence of viable tumour cells in the excised tumour thrombus upon histological examination, despite preoperative chemotherapy, as seen in 8/11 (72.7%) of our patients, does not appear to be detrimental with regard to local recurrence in the vascular compartment. Similarly, Shamberger et al. [10] have reported no increased incidence of relapse in 18 patients with incomplete removal of tumour thrombus. This information possibly indicates that achieving ‘gross clearance’ is preferable to heroic attempts at extensive clearance of caval and atrial lumen of all tumour thrombus at the cost of jeopardizing the subsequent satisfactory repair of the IVC and prolonging time spent on CPB and DHCA, and is safe in the long term. There appear to be no long-term detrimental effects from the insertion of a bovine graft for extensive IVC repair. Although we advocate the use of aspirin as an anti-thrombotic measure, information on patient compliance in this regard is lacking. This and the documentation of graft patency will be the subject of a future study. Any possible consequences from thrombotic occlusion of the caval neo-lumen are perhaps obviated by the development of adequate retroperitoneal collaterals in these children. In conclusion, although the treatment of Wilms’ tumour with persistent cavo-atrial tumour thrombus remains a surgical challenge, aggressive treatment is warranted. The use of pre- and postoperative chemotherapy, a multidisciplinary approach to surgical decision making with close cooperation between oncologist, paediatric urologist and cardio-thoracic surgeons, and the use of radiotherapy has improved the outcome for these children. Our experience suggests that a combined abdomino-thoracic approach by the urologist and cardiac surgeon, with judicious use of CPB and DHCA, allows optimal surgical excision, and satisfactory restoration of inferior vena caval lumen with a bovine pericardial patch graft offers the most benefit for both immediate and long-term outcome measures.
Acknowledgements We wish to thank Dr D. Roebuck, Consultant Interventional Radiologist, for contributing the CT images (Fig. 1A and B) that were used in this manuscript.
Wilms’ tumour with persistent intravascular extension
References [1] Ritchey ML, Kelalis PP, Breslow N, Offord KP, Shochat SJ, D’Angio GJ. Intracaval and atrial involvement with nephroblastoma: review of National Wilms Tumor Study-3. J Urol 1988;140:1113e8. [2] Akyuz C, Emir S, Buyukpamukcu N, Atahan L, Caglar M, Kutluk T, et al. Cavoatrial tumor extension in children with Wilms tumor: a retrospective review of 17 children in a single center. Pediatr Hematol Oncol 2005;27:267e9. [3] Nakayama DK, Norkool P, deLorimier AA, O’Neill Jr JA, D’Angio GJ. Intracardiac extension of Wilms’ tumor. A report of the National Wilms’ Tumor Study. Ann Surg 1986; 204:693e7. [4] Ritchey ML, Kelalis PP, Breslow N, Etzioni R, Evans I, Haase GM, et al. Surgical complications after nephrectomy for Wilms’ tumor. Surg Gynecol Obstet 1992;175:507e14. [5] Kogan SJ, Marans H, Santorineau M, Schneider K, Reda E, Levitt SB. Successful treatment of renal vein and vena caval extension of nephroblastoma by preoperative chemotherapy. J Urol 1986;136:312e7. [6] Crombleholme TM, Jacir NN, Rosenfield CG, Lew S, Harris BH. Preoperative chemotherapy in the management of intracaval extension of Wilms’ tumor. J Pediatr Surg 1994;29:229e31. [7] Oberholzer HF, Falkson G, De Jager LC. Successful management of inferior vena cava and right atrial nephroblastoma tumor thrombus with preoperative chemotherapy. Med Pediatr Oncol 1992;20:61e3. [8] Ritchey ML, Shamberger RC, Haase G, Horwitz J, Bergemann T, Breslow NE. Surgical complications after primary nephrectomy for Wilms’ tumor: report from the National Wilms’ Tumor Study Group. J Am Coll Surg 200;192:63e8.
445
[9] Szavay P, Luithle T, Semler O, Graf N, Fuchs J. Surgery of cavoatrial tumor thrombus in nephroblastoma: a report of the SIOP/GPOH study. Pediatr Blood Cancer 2004;43: 40e5. [10] Shamberger RC, Ritchey ML, Haase GM, Bergemann TL, Loechelt-Yoshioka T, Breslow NE, et al. Intravascular extension of Wilms tumor. Ann Surg 2001;234:116e21. [11] Lodge AJ, Jaggers J, Adams D, Rice HE. Vascular control for resection of suprahepatic intracaval Wilms’ tumour: technical considerations. J Pediatr Surg 2000;35:1836e7. [12] Wypij D, Newburger JW, Rappaport LA, duPlessis AJ, Jonas RA, Wernovsky G, et al. The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003;126:1397e403. [13] Svensson LG, Crawford ES, Hess KR, Coselli JS, Raskin S, Shenaq SA, et al. Deep hypothermia with circulatory arrest. Determinants of stroke and early mortality in 656 patients. J Thorac Cardiovasc Surg 1993;106:19e31. [14] Chiappini B, Savini C, Marinelli G, Suarez SM, Di Eusanio M, Fiorani V, et al. Cavoatrial tumor thrombus: single-stage surgical approach with profound hypothermia and circulatory arrest, including a review of the literature. J Thorac Cardiovasc Surg 2002;124:684e8. [15] Schettini ST, da Fonseca JH, Abib SC, Telles CA, Haber MX, Rizzo MF, et al. Management of Wilms’ tumor with intracardiac extension. Pediatr Surg Int 2000;16:529e32. [16] Sripathi V, Muralidharan KV, Ramesh S, Muralinath S. Wilms’ tumor with vena caval, atrial, and middle hepatic vein tumor thrombus. Pediatr Surg Int 2000;16:447e8. [17] Pannek J, Goepel M, Kremens B, Otto T, Sadony V. Surgical management of Wilms tumor with intracardiac neoplastic extension. Thorac Cardiovasc Surg 1994;42:108e11.