Little is known on the natural history of positive surgical margins (PSMs) in partial nephrectomy (PN). Accumulating data suggest that secondary nephrectomy might not be necessary in all patients with PSMs after PN.
Provide an overview on incidence and risk factors for PSMs after partial nephrectomy and on the rate of local and distant disease recurrence related to PSMs. We also provide recommendations on how to avoid and how to treat PSMs after PN.
A nonsystematic literature research was based on Medline, Scopus, and Web of Science queries on these keywords: nephron-sparing surgery, partial nephrectomy/ies, and margin. Only human studies (original research) published in English were included.
PSMs are present in 0–7% of patients after open PN, in 0.7–4% after laparoscopic PN, and in 3.9–5.7% after robot-assisted PN. The thickness of healthy parenchyma surrounding the tumour is irrelevant as long as complete tumour removal is achieved. The coincidence of a highly malignant tumour and PSM increases the risk of local recurrence. Intermediate follow-up data indicate that the vast majority of patients with PSMs will not experience local or distant tumour recurrence. Frozen-section analysis for evaluation of resection margins during PN is of minor clinical significance, as the surgeon's gross assessment of macroscopically negative margins provides reliable results.
PSMs in PN are rare. As indicated by intermediate follow-up data, the majority of patients with PSMs after PN remain without disease recurrence, and a surveillance strategy seems preferable to surgical reintervention.
Keywords: Margin, Partial nephrectomy, Nephron-sparing surgery, Frozen section, Recurrence.
A lower risk of chronic kidney disease (CKD), as expected from nephron-sparing surgery, reduces the risk of cardiovascular events and directly translates into improved overall survival , , and . The risk of incomplete tumour removal, however, is of concern with PN. Little is known of the natural history of positive surgical margins (PSMs) in kidney cancer surgery, although it seems that the majority of these patients neither progress locally nor experience distant metastasis . Although complete tumour removal is an oncologic principle of paramount importance, accumulating data suggest that secondary nephrectomy might not be the treatment of choice in all patients with PSMs after PN. However, it is unclear how to define the patient at risk for a PSM and for disease recurrence after PSM and if the incidence of PSM is related to the surgical approach or technique (eg, open vs laparoscopic vs robot-assisted PN, simple tumour enucleation).
This review provides a comprehensive overview of incidence and significance of PSMs after nephron-sparing surgery for renal tumours. We outline information on the risk factors for PSMs and highlight the rate of local and distant disease recurrence related to a PSM. Finally, this review provides recommendations on how to avoid and how to treat PSMs after nephron-sparing surgery.
2. Evidence acquisition
A comprehensive nonsystematic literature research was based on free-text queries on Medline, Scopus, and Web of Science on the combination of the keywords nephron sparing surgery, partial nephrectomy/ies, and margin from 1 January 2001 to 10 July 2011. Only human studies (original research) published in English were included. Reference lists in the respective articles were surveyed for related literature. Review articles were screened for missing articles but excluded from the final reference list, as were meeting abstracts and articles on paediatric surgery. Because of the absence of randomised trials and the low prevalence of PSMs, weighted cumulative analysis and comparative analyses were not performed.
3. Evidence synthesis
Articles including larger cohorts of patients with PSMs after PN are scarce. Therefore, conclusions were mainly based on small series of patients with limited follow-up. As not a single randomised controlled trial is available, the included studies (n
3.1. Incidence and risk of positive surgical margins after partial nephrectomy
A PSM after PN is a rare event. In the current literature, overall rates of PSMs range from 0% to 7% , , , , , and . According to the surgical approach, PSM rates are 0–7% after open PN (OPN), 0.7–4% after laparoscopic PN (LPN), and 3.9–5.7% after robot-assisted PN (RAPN) (Table 1). Few authors have reported PSM rates as high as 18% in selected patient cohorts containing larger tumours or undergoing PN for imperative indications (Table 2).
|Study||Patient s, no.||Surgical technique||Tumor size, cm||PSM rate, %||Comment|
|Patard et al. ||1048||OPN||3.4||1.5 (<4 cm) 1.3 (>4 cm)||Similar PSM rates in tumours <4
|Kwon et al. ||777||OPN||2.6||7||Higher local recurrence rate in highly malignant tumours and PSM|
|Saranchuk et al. ||54||OPN||3.4||15||Solitary kidneys|
|Zigeuner et al. ||117||OPN||3.4||5||PSM do not reliably predict residual tumour tissue|
|Van Poppel et al. ||268||OPN||5.1||Tumor size <5
|Bernhard et al. ||809||OPN||3.4||1.5||PSM are independent risk factor for ipsilateral tumor recurrence (8.1% LPN included)|
|Duvdevani et al. ||301||OPN||3.6/3.2*||0.6/4.2*||No vascular occlusion may increase risk of PSM|
|Duvdevani et al. ||301||OPN||3.6||2||Accuracy of frozen-section analysis is questionable|
|Lifshitz et al. ||184||LPN||2.5||3||PSM rate similar in first and last 50 patients of surgeon experience|
|Porpiglia et al. ||90||LPN||3.1||4.4||Higher PSM rate in patients with complications|
|Permpongkosol et al. ||511||LPN||2.8||1.8||PSM does not necessarily indicate residual disease|
|Link et al. ||223||LPN||2.6||3.5||PSM rate comparable to open series of PN|
|Porpiglia et al. ||100||LPN||2.4 (<4 cm) 5 (<4 cm)||3.9 (<4 cm) 0.3 (>4 cm)||Comparable PSM rates in tumours <4
|Breda et al. ||855||LPN||2.7||2.5||Discrepancy between frozen-section and final pathology|
|Frank et al. ||363||LPN||3.0 (central tumor) 2.4 (peripheral tumor)||0.8 (central tumor) 0.7 (peripheral tumor)||PSM status similar in central and peripheral tumors|
|Venkatesh et al. ||123||LPN||2.6||2.5||PSM rate during initial surgeon experience|
|Scoll et al. ||100||RAPN||2.8||5.7||–|
|Rogers et al. ||148||RAPN||2.8||4||–|
|Mottrie et al. ||62||RAPN||2.8||2||–|
|Gill et al. ||200||LPN||2.8||3.0||–|
|Gill et al. ||1800||LPN||2.6||2.9||PSM rate for cancer: 1.6 (OPN), 1.0% (LPN)|
|Marszalek et al. ||200||LPN||2.8||4||Similar rates of PSM in matched-pair comparison of LPN and OPN|
|Gong et al. ||153||LPN||2.9||1.3||PSM rate comparable in LPN and OPN|
|Benway et al. ||247||LPN||2.5||1.0||A learning curve exists for RAPN with regard to margin status|
|Yossepowitch et al. ||1390||NA||3.5||5.5||Select patients with a PSM can be offered vigilant monitoring|
|Study||Patients with imperative indication, no.||Patients with PSM, no.||Follow-up, mo||Tumor size, cm||Patients with local recurrence, no.||Patients with distant metastasis, no.|
|Saranchuk et al. ||54||8||40.5||3.4||2||3|
|Peycelon et al. ||40||11||70.7||5.6||1||2|
|Lee at al ||30||5||29.0||3.3||2||NA|
* Nonclamping/clamping group.
3.2. Surgical technique
3.2.1. Does the surgical approach have any influence on the occurrence of positive surgical margins?
PN is performed by open, laparoscopic, and, in recent series, robot-assisted surgery. Several studies have shown the oncologic efficacy of OPN with regard to surgical margin (SM) status , , , , and . In recent years, LPN, either by the trans- or retroperitoneal approach, became increasingly available. Although LPN reduces the morbidity of the procedure and allows for quicker reconvalescence, the demanding technical complexity of LPN requires an experienced laparoscopic surgeon. Few comparative studies provide data on OPN and LPN with regard to SM status (Table 1); no randomised trials are available. The largest multi-institutional study by far, performed by Gill et al, revealed comparable PSM rates of 1.3% and 2.8% in OPN and LPN . Similar results were reported by others , , , , and . As an evolution of the laparoscopic technique, RAPN is gaining acceptance. Improved visualisation of the surgical field and the advantage of fully articulating instruments seem to eclipse the adherent economic burden. PSM rates after RAPN are within the range of OPN and LPN , , , , and .
The impact of the learning curve on PSM rate is difficult to assess; more demanding tumours will be approached with increasing experience. An impact of the learning curve of PN on PSM rate cannot be derived from initial institutional results , , , and .
3.2.2. Thickness of healthy parenchyma surrounding the tumour/tumour enucleation
Historically, a 1-cm rim of regular renal tissue was recommended to ensure complete tumour removal . Meanwhile, accumulating data underscore that a minimum of regular renal parenchyma covering the tumour provides the oncologic safety required for PN without an additional risk of complications and the unnecessary loss of healthy tissue  and . Furthermore, margin status is the most important end point , , , , , , , , and ; safety margin thickness does not correlate with disease progression . The 2011 edition of the European Association of Urology guidelines on the treatment of localised renal cell cancer (RCC) also considers a minimal tumour-free margin sufficient to avoid local tumour recurrence .
Simple tumour enucleation yielded oncologic results comparable to PN , , , and , although a prospective randomised trial comparing PN and simple enucleation of renal masses has not been conducted. During tumour enucleation, a natural cleavage plane between the tumour pseudocapsule and regular kidney parenchyma allows for blunt dissection without entering the tumour . Even in the case of neoplastic pseudocapsule invasion, a thin layer of chronic inflammatory tissue may still prevent a PSM . However, a pseudocapsule serving as landmark for simple enucleation will be missing in some tumours . These patients are exposed to the risk of a PSM by an attempted tumour enucleation. The largest retrospective study to date on enucleation of renal masses was conducted by Minervini et al.  and compared 537 patients after tumour enucleation to 982 patients after standard PN at a median follow-up of 54.4 mo. The 10-yr cancer-specific survival was similar in both groups, but the PSM rate was higher after PN (3.4% vs 0.2%) . Multi-institutional long-term follow-up data are awaited to confirm these results.
3.2.3. Influence of imperative versus elective indication
Patients with an imperative indication for PN present often with larger tumours, unfavourable tumour localisation, and tumours that otherwise would have undergone radical nephrectomy. Therefore, a higher incidence of PSM is observed in imperative indications (Table 2). In a series of 54 patients with solitary kidneys undergoing OPN for renal masses, Saranchuk et al. reported a PSM rate of 15% .
3.2.4. Positive surgical margins and tumour size
The correlation of tumour size and PSM rate is still subject to debate. Patard and others found comparable PSM rates in tumours smaller and larger than 4
3.2.5. Positive surgical margins and tumour localisation
Studies on the relationship of PSM and tumour localisation are rare , , , and . PSM rates for central and peripheral tumours are either comparable  or higher in central tumours  and . In a retrospective multicentre analysis, Bensalah et al. compared 111 patients with PSMs to 664 patients with negative SM (NSM). Centrally located tumours were present in 29% of patients with PSMs but in only 9.1% of those with NSM . None of the studies available applied reproducible nephrometry scores  and , a useful tool that will improve comparability of future studies. Therefore, conclusions that can be drawn are limited by the arbitrary definition of tumour localisation. After all, the complexity of PN seems to translate into SM status, as small and endophytic tumours may be more demanding of the surgeon's skills than larger exophytic ones.
3.3. Impact of histologic subtype
Only two studies present data on the relation of PSM and tumour histology. In their analysis of 777 OPN, Kwon et al. found comparable PSM rates in tumours with low (oncocytoma, angiomyolipoma, papillary RCC type I, chromophobe RCC, and other benign lesions) and high malignant potential (clear cell RCC, collecting-duct carcinoma, papillary RCC type II, and tumours with sarcomatoid differentiation) based on the Heidelberg classification of histologic subtypes . Tumour histology was not predictive of SM status. In patients with PSMs, local or distant disease recurrence (n
3.4. Positive surgical margins, tumour recurrence, and survival
The results of nephron-sparing surgery for small RCC are excellent; however, the risk of disease recurrence, although minimal, is of concern. Whether or not a PSM is a risk factor for disease recurrence after PN has been controversial, but results are comparable in most series: PSMs increase the risk of disease recurrence, but influence on survival is limited  and  (Table 3). One of the largest studies on patients with PSMs after PN did not observe an increased risk of local recurrence or metastatic progression (median follow-up: 3.4 yr) . The only predictor of local and distant disease recurrence was tumour size. Also at longer follow-up (80.5 mo), patients with PSMs did not experience any recurrences . However, other investigators reported higher recurrence rates with PSMs , , and . A recent analysis of 809 PN identified PSM as an independent risk factor for ipsilateral tumour recurrence . The PSM rate in this analysis was 1.5%. One-third of those patients developed local recurrence (median time to detection: 23.2 mo). Another survey of 775 patients after PN also observed an increased risk of and a shorter time to disease recurrence with PSM . However, cancer-specific and overall survival were not affected by margin status (mean follow-up: 37 mo). The combination of highly malignant tumours and PSMs may also increase the risk of local recurrence . In summary, PSMs after PN harbour an increased risk of disease recurrence, especially in patients with tumours of high malignant potential. The vast majority of patients with PSMs do not experience local or distant tumour recurrence, but only intermediate follow-up data are available. Given a vigilant monitoring protocol, surveillance seems to be a viable alternative to salvage surgery in those patients, thereby preventing overtreatment and further renal function loss.
|Study||Follow-up, mo||Patients with PSM, no.||Patients with local recurrence, no.||Patients with distant metastasis, no.||Patients with NED, no.||Comment|
|Yossepowitch et al. ||39.6||77||NA||NA||NA||PSM not associated with increased risk of local recurrence or metastatic disease|
|Kwon et al. ||22||57||2||2||53||Higher local recurrence rate in highly malignant tumours with PSM|
|Lifshitz et al. ||18||6||0||0||6||PSM rate in initial and advanced experience|
|Zigeuner et al. ||76/85*||6||2||3||3||PSM are frequently caused artificially|
|Scoll et al. ||12.7||5||0||0||5||Patients after RAPN|
|Gill et al. ||22.8||21||1||1||20||Results of 1800 patients undergoing LPN/OPN|
|Permpongkosol et al. ||32||7||0||1||6||PSM do not necessarily indicate residual disease|
|Benway et al. ||26||7||0||0||7||Patients after RAPN|
|Benway et al. ||48/12||1/5||0||0||6||LPN/RAPN|
|Piper et al. ||60||7||0||2||5||Questions the necessity of 1-cm margin width|
|Minervini et al. ||>51||26||1||NA||NA||Patients after standard PN and simple enucleation|
|Raz et al. ||40||4||0||0||4||Avoid nephrectomy as response to PSM|
|Bensalah et al. ||37||111||7||4||NA||PSM occur more frequently in imperative cases. PSM associated with increased risk of recurrence, but do not affect CSS|
|Desai et at ||56.4||5||0||0||5||Surveillance in selected patients may be adequate without sacrificing oncologic control|
|Lopez-Costea et al. ||80.5||9||0||0||9||Manage microscopic PSM conservatively|
|Ray et al. ||24.0||8||0||0||8||OPN|
|Duvdevani et al. ||53.4||4||1||0||3||Accuracy of frozen sections in PN questionable|
* Elective versus imperative indication group.
3.5. How to avoid a positive surgical margin
Several circumstances might pave the way for the occurrence of a PSM, such as impaired intraoperative visibility, poor orientation, and rather small but deeply infiltrating tumours. Small, entirely exophytic tumours may be safely resected without hilar clamping, although some authors underline the role of temporary vascular occlusion to improve visualisation of the resection margin , , and . However, no difference in PSM rate was observed in a recent analysis comparing PN with and without hilar clamping . Another method to achieve NSM is ultrasound-guided placement of a curved needle around the intraparenchymal portion of the tumour , helping the laparoscopic surgeon remain in the resection plane. However, PSMs may still occur laterally to the needle's plane, limiting the clinical benefit of this method.
Endophytic growth pattern or adherent perinephric fat may obviate tumour localisation. In such cases, intraoperative ultrasound and, recently, near-infrared fluorescence imaging can be valuable in correctly defining tumour extent, intended resection line, and renal vasculature  and . Augmented reality navigation systems are able to superimpose virtually created and real-time images, thereby facilitating laparoscopy port placement and identification of tumour and adjacent structures . Such auxiliaries may potentially increase the precision of PN in the future, although their impact on PSM rates remains to be determined.
3.6. Frozen section analysis: useful or useless?
Methods for intraoperative evaluation of SMs are routine frozen-section analysis, on-site pathologic examination, gross inspection of the resection margin by the surgeon, and on-demand frozen section in ambiguous cases. The accuracy of frozen-section analysis, in particular, met with criticism due to intermittent false-negative or inconclusive results that did not correlate well with final pathology , , , , , and . Accurate diagnosis is also hampered by insufficient minute fragments of tissue sent to the pathologist for frozen-section analysis . Tumour-bed biopsies represent only a small fraction of the resection margin and, in general, deliver unreliable results. In select cases, frozen-section analysis of suspicious areas of the resected specimen may improve diagnostic accuracy . A robust accordance exists between gross SM interpretation by the surgeon and final histologic analysis . The surgeon's gross interpretations provide reliable results sufficient for intraoperative decision making and particularly for avoiding false-negative results. Furthermore, with LPN and RAPN, tumour extraction is usually the final step after renal repair, which obviates the time-consuming process of frozen-section analysis. Finally, an additional safety margin created by intensive fulguration of the resection bed by cautery or argon beam may render PSMs clinically insignificant. Against this background, routine frozen-section analysis delivers no additional information of clinical significance.
3.7. Management of positive surgical margins
Disease recurrence rate after PSMs is low and impact on survival is limited. When counselling patients with PSMs, all therapeutic options—radical nephrectomy, repeat PN, energy ablation, and observation—should be taken into consideration. Radical nephrectomy may adequately address a PSM from an oncologic point of view, but the nephrectomy specimen after PN will only contain tumour remnants in 6.9% to 15% of cases  and . In addition, radical nephrectomy will sacrifice well functioning renal tissue, thus elevating the risk of CKD, which, in turn, leads to decreased survival  and . For these reasons, radical nephrectomy after PN with PSM is not the optimal strategy. Repeat PN to achieve NSM is aimed at preserving the renal unit, but it is technically demanding and may result in loss of the kidney due to difficulties such as intraoperative bleeding or surgical complications. In addition, as with radical nephrectomy, viable tumour will rarely be found in the resected tissue , , and . However, repeat PN may be considered with tumours presenting aggressive or high-grade features (eg, Fuhrman grade III–IV, papillary RCC type II, and sarcomatoid differentiation). Radiofrequency ablation and cryotherapy of PSMs after PN are minimally invasive treatment options, but both share the same disadvantages: No tissue is retrieved for histologic evaluation and follow-up is hampered by artificial tissue alterations. According to the data available, watchful waiting seems to be the most appropriate option for the management of PSMs after PN, preserving a maximum of renal units and sparing the patient needless surgery in the majority of cases  and . The few patients affected by disease recurrence will benefit from a vigilant surveillance protocol enabling early salvage treatment. However, no validated follow-up scheme exists for patients with PSMs after PN.
The achievement of NSMs as a principle of oncologic surgery is of utmost importance and remains the preferential aim of the uro-oncologic surgeon. PSMs in PN occur in 0–7% of cases and seem associated with smaller and endophytic tumours. Gross evaluation of resection margins by the surgeon delivers reliable results, rendering routine frozen-section analysis clinically superfluous. A PSM raises the risk of disease recurrence, especially in tumours of high malignant potential. The lack of large-scale data and of prospective trials including nephrometry scores and long-term follow-up obviates a definitive statement. Intermediate follow-up data available indicate that the majority of patients with PSMs after PN will not experience disease recurrence. Therefore, a surveillance strategy with adherence to a vigilant follow-up protocol seems to be preferable over surgical reintervention.
Study concept and design: Marszalek, Madersbacher, Van Poppel.
Acquisition of data: Marszalek, Carini, Knüchel, Patard, Van Poppel.
Analysis and interpretation of data: Marszalek, Carini, Knüchel, Madersbacher, Patard, Van Poppel.
Drafting of the manuscript: Marszalek.
Critical revision of the manuscript for important intellectual content: Carini, Chlosta, Jeschke, Kirkali, Knüchel, Madersbacher, Patard, Van Poppel.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Marszalek, Van Poppel.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
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a Department of Urology and Andrology, Donauspital, Vienna, Austria
b Department of Urology, Graz Medical University, Graz, Austria
c Department of Urology, University of Florence, Careggi Hospital, Florence, Italy
d Department of Urology, Institute of Oncology, Kielce, Poland
e Department of Urology, Klagenfurt General Hospital, Klagenfurt, Austria
f Department of Urology, Dokuz Eylul University School of Medicine, Izmir, Turkey
g Institute of Pathology, Aachen University, Aachen, Germany
h Department of Urology, Bicêtre Hospital, Paris XI University, Kremlin Bicêtre, France
i Department of Urology, University Hospital Leuven, Leuven, Belgium
© 2011 Published by Elsevier B.V.