|Year : 2019 | Volume
| Issue : 10 | Page : 1396-1402
The effect of surgical margin on cancer-specific survival in patients treated with nephron-sparing surgery
F Kizilay1, U Eskidemir1, T Bahceci1, A Simsir1, H Ozdemir2, B Sarsik2, B Turna1
1 Department of Urology, Ege University School of Medicine, Bornova, İzmir, Turkey
2 Department of Pathology, Ege University School of Medicine, Bornova, İzmir, Turkey
|Date of Acceptance||03-Jun-2019|
|Date of Web Publication||14-Oct-2019|
Dr. F Kizilay
Department of Urology, Ege University School of Medicine, Bornova, İzmir
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Nephron-sparing surgery (NSS) is currently the recommended treatment modality for selected renal tumors. The prognostic significance of positive surgical margin (PSM) and surgical margin width (SMW) after NSS is controversial. Aim: To evaluate the effect of PSM and SMW on cancer-specific survival (CSS) in patients who underwent NSS. Materials and Methods: The pathological samples of 142 patients who underwent NSS were reviewed. Patients were divided into two groups with PSM and negative surgical margin (NSM), and after that those with PSM were divided into two groups according to SMW as those with 0.1–2 mm and those >2 mm. CSS was calculated using Kaplan–Meier method. Cox regression analysis was used to adjust the clinicopathologic variables. A P value < 0.05 was considered statistically significant. Results: Local recurrence rate and distant metastasis rate were higher in patients with PSMs than those with NSMs (P = 0.018 and P = 0.039, respectively). However, there was no significant difference between the two groups in terms of CSS. In the group with SMW 0.1–2 mm, the tumor diameter was longer (P = 0.018), enucleation number was higher (P = 0.026), and local recurrence was higher (P = 0.034) than the group with SMW > 2 mm. There was no significant difference between the two groups in terms of CSS. Conclusion: In patients who underwent NSS, PSMs and SMWs have a negative effect on local recurrence but have no significant effect on CSS.
Keywords: Nephron-sparing surgery, pathology, prognosis, renal cell carcinoma, survival
|How to cite this article:|
Kizilay F, Eskidemir U, Bahceci T, Simsir A, Ozdemir H, Sarsik B, Turna B. The effect of surgical margin on cancer-specific survival in patients treated with nephron-sparing surgery. Niger J Clin Pract 2019;22:1396-402
|How to cite this URL:|
Kizilay F, Eskidemir U, Bahceci T, Simsir A, Ozdemir H, Sarsik B, Turna B. The effect of surgical margin on cancer-specific survival in patients treated with nephron-sparing surgery. Niger J Clin Pract [serial online] 2019 [cited 2019 Dec 15];22:1396-402. Available from: http://www.njcponline.com/text.asp?2019/22/10/1396/269014
| Introduction|| |
Renal cell carcinoma (RCC) accounts for 2%–3% of all cancers. Moreover, it is the third most common urological cancer. Recent technological developments in radiological imaging methods have increased the rate of detection of renal tumors, especially incidental tumors and tumors less than 4 cm in diameter. As the number of these incidental and small tumors has increased, so has the number of nephron-sparing surgeries (NSSs).
NSS remains the preferred surgical therapy for renal masses less than 7 cm in diameter when NSS is technically feasible. NSS is also indicated for tumors with a diameter >7 cm in the context of imperative indications. NSS is recommended especially in cases of bilateral renal tumors, inherited tumors (such as Birt–Hogg–Dube syndrome, Von Hippel–Lindau, and hereditary papillary RCC), solitary renal tumors, or in cases where the health of the other kidney is threatened. NSS can be performed by open or laparoscopic/robotic methods.
There are three feasible nephron-sparing surgical techniques (based on tumor location): tumor enucleation (TE), polar nephrectomy, and hemi- nephrectomy. Every technique used for NSS risks the possibility of local recurrence due to positive margins. The purpose of enucleation is to maintain a maximum amount of healthy kidney tissue while providing negative surgical margin (NSM) and completely removing the tumorous tissue. Tumor excision with a rim of normal tissue is a fundamental, unanimously accepted principle in surgical oncology. Historically, a 10-mm rim of regular renal tissue was recommended to ensure complete tumor removal; contemporary data, however, suggest that margins <5 mm or even TE both result in similarly favorable outcomes., In the area of renal parenchyma preservation, TE offers the smallest possible margin of excised tissue. Regardless of the surgical technique and the tumor dimension, the proper width of a safe, healthy margin after NSS that avoids a positive surgical margin (PSM) and disease progression has been a matter of remarkable debate in the literature.
In this study, we aimed to evaluate the relationship between various histopathologic features (histopathological type, grade, tumor diameter, surgical margin positivity, and width) of tumors and cancer-specific survival (CSS) in patients treated with NSS. In particular, we aimed to evaluate the prognostic significance of surgical margin positivity and width, which is still a controversial issue.
| Materials and Methods|| |
Patient selection and study protocol
The pathological samples of 142 patients who applied to our urology clinic with a prediagnosis of kidney tumor and underwent NSS between January 2015 and June 2017 were reviewed. A total of 17 patients were excluded from the study: these cases had definitive benign histopathology angiomyolipoma (n = 7), cystic nephroma (n = 1), or oncocytoma (n = 9); the remaining 125 patients with malignant histopathology were included in the study. Patients who underwent NSS, regardless of the method (open, laparoscopic, or robotic) and had a histopathologic diagnosis of malignant tumor during the study period, were included. The exclusion criteria were radical nephrectomy application, grade T2 tumors, or tumor detection in benign histopathology.
Informed and written consent was obtained from all patients included in the study, and the consent forms included approval for their medical information to be used for scientific studies, provided that the patients' identifying information was removed. All renal specimens were evaluated, within the framework of the study protocol, by pathologists who were experienced in uropathology and worked in the pathology clinic of our hospital. Histologic classification of the primary tumor was performed according to the guidelines of the Union Internationale Contre le Cancer and the American Joint Committee on Cancer. The patients' hematoxylin and eosin–stained slides were re-evaluated in terms of the correlation of tumor surgical margins with tumor histological type, grade, stage, and recurrence/metastasis findings. A picture of a right partial nephrectomy and tumor histologic featuress and a typical chromophobe RCC confined to the pseudocapsule are shown in [Figure 1] and [Figure 2].
|Figure 1: Gross picture of right partial nephrectomy and histologic features of the tumor. (a) The tumor is 4 × 3.5 × 3 cm in size, located in the upper pole (arrow), and confined to the renal parenchyma. (b) The tumor cells have clear cytoplasm and round nuclei, typical of renal cell carcinoma of the clear cell type. The Fuhrman nuclear grade is 2/4 (H and E stain, ×200)|
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|Figure 2: Typical of renal cell carcinoma of the chromophobe type and confined to the pseudocapsule (arrow) (H and E stain, ×200)|
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The patient's age and gender, CSS data, and the patient's tumor's histopathology, Fuhrman grade, diameter, surgical margin width (SMW), enucleation status, local recurrence status, and distant metastasis status were obtained from patient files and the hospital registry system.
The primary end-point of the study was CSS, defined as the time from surgery to death due to cancer or disease-related complications. Chi-square test and t-tests were used for the analysis of categorical and continuous variables. Cox regression analysis was performed to evaluate the effect of SMW and other clinicopathologic variables on CSS. Multivariate analysis was performed to determine the effect of variables with P < 0.05 in univariate analysis. Survival analysis was performed using Kaplan–Meier method. A P value < 0.05 was considered statistically significant. The SPSS 23.0 package program was used for the statistical analyses (SPSS, Chicago, IL, USA).
| Results|| |
NSS was applied to 125 patients with a prediagnosis of local renal tumor. The mean follow-up period was 55.35 ± 4.8 months. The majority of patients were male (64%). The most common tumor histopathology was clear cell RCC (66.4%). The most common Fuhrman grade was 2 (56%). The mean tumor diameter and tumor margin were 31.12 ± 6.4 and 3.2 ± 0.4 mm, respectively. Enucleation was performed in 38.4% of the patients. Sixteen patients (12.8%) had local recurrences during the follow-up period and three patients (2.4%) had distant metastasis. The mean survival time was 47.22 ± 8.6 months. Six patients (4.8%) died during follow-up. The demographic and clinicopathologic characteristics of the patients are summarized in [Table 1].
|Table 1: Demographic and clinicopathologic data of patients who underwent nephron-sparing surgery|
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The surgical margin was negative in the majority of patients (110 vs. 15). The mean tumor diameter of patients with PSMs was significantly larger than those with NSMs (41.44 vs. 32.28 mm, P = 0.026) and the rate of enucleation was higher in the PSM group (73.3% vs. 33.6%, P = 0.035). The local recurrence rate and distant metastasis rate were also higher in patients with PSMs (33.3% vs. 5.5%, P = 0.018 and 13.3% vs. 0.1%, P = 0.039, respectively); however, there was no significant difference between the two groups in terms of CSS (P = 0.24). The comparison of the clinicopathologic data of patients with NSMs and PSMs is shown in [Table 2].
|Table 2: Comparison of clinicopathologic data of patients with positive and negative surgical margins|
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The patients were divided into two groups according to the SMW: 0.1–2 mm (n = 59) and >2 mm (n = 51). Patients with SMWs shorter than 2 mm had significantly longer tumor diameters (38.46 vs. 28.12 mm, P = 0.018), a higher rate of enucleation (32 vs. 5, P = 0.026), and more frequent local tumor recurrence (5 vs. 1, P = 0.034). Immediate complementary (radical) nephrectomy was applied to all patients with local recurrence at follow-up. The mean CSS of the two groups was similar (P = 0.61). The comparison of the clinicopathologic features of patients with SMWs of 0.1–2 mm versus those with widths >2 mm is given in [Table 3].
|Table 3: Comparison of clinicopathologic features of patients with surgical margin width 0.1-2 mm vs. >2 mm|
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Multivariate regression analysis was performed for variables that were statistically significant in the univariate analysis. Tumor diameter, enucleation, and SMW <2 mm were negative prognostic factors for local recurrence (P = 0.035, P = 0.024, and P = 0.044, respectively). The multivariate regression analysis for CSS is summarized in [Table 4].
|Table 4: Multivariate Cox regression analysis of risk factors predicting local recurrence|
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For survival analysis, two groups of patients [with an SMWs of 0.1–2 mm (n = 59) or SMWs >2 mm (n = 51)] were evaluated. Kaplan–Meier analysis showed no significant difference between the 0.1–2 mm SMW group and the >2 mm SMW group in terms of mean CSS (42.18 vs. 48.91 months, P = 0.61). The Kaplan–Meier survival curve demonstrating the CSS difference according to the SMW characteristic of the entire cohort is shown in [Figure 3].
|Figure 3: Kaplan–Meier survival curve showing overall cancer-specific survival according to surgical margin width 0.1–2 mm and >2 mm in the entire cohort|
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| Discussion|| |
In recent years, NSS has replaced radical nephrectomy in the treatment of locally confined RCC and has become the standard method for appropriate cases.,,, The main reasons for this revolution in management are NSS' better preservation of renal function and decreased cardiovascular morbidity in the postoperative period compared to other surgeries., In addition, the oncologic results of both methods appear to be similar and the perioperative morbidity of NSS is slightly higher than that of radical nephrectomy., As a result of the increased frequency of NSS and TEs, tumor cells appear at the surgical margin (PSM) in the final histopathological evaluation of 0%–7% of surgical specimens. In this study, we investigated the prognostic significance of histopathologically positive PSM and SMW for local recurrence, metastasis, and CSS in patients who underwent NSS for renal tumors.
Histopathologic examination of the majority of our patient cohort showed NSMs (88%). Primarily, we made a clinicopathological comparison between the patients with NSMs and those with PSMs. Thereafter, patients with NSMs were divided into two groups (SMW 0.1–2 mm and SMW >2 mm) and the clinicopathological data between these two groups were compared. There is still no consensus on the management of patients with PSMs; some practitioners have performed urgent or late complete (radical) nephrectomy in patients with PSMs,, whereas others have followed up these patients. In some studies, the cancer and overall survival rates of patients with PSMs and NSMs were similar, whereas in some cases, a PSM was associated with significantly higher recurrence and metastasis rates., In our cohort, patients with PSMs had a worse local recurrence and distant metastasis rate, but this difference was not reflected in CSS rates.
In their 775-case trial, Bensalah et al. showed that if the tumor is completely resected, the thickness of the surgical margin does not affect the local recurrence rate. Sutherland et al. investigated the effect of the surgical margin size on recurrence in 44 patients who underwent NSS; they did not detect local recurrence in any patient with a negative parenchymal margin. They detected multiple local and metastatic recurrences in one of the three cases with PSMs and emphasized that a normal renal parenchyma smaller than 5 mm should be removed during NSS for local RCC treatment. In the study by Castilla et al., the patients were divided into four groups according to the tumors' resection margins (SMWs of <1 mm, 1.01–2 mm, 2.01–2.5 mm, or >2.5 mm) and they could not detect any significant differences between the groups in terms of long-term disease progression rates. They concluded that for a complete local excision of RCC, a histological tumor-free margin is much more important than the margin width. In our study, although we found more local recurrence in the cohort with surgical margins of less than 2 mm than in the group with surgical margins >2 mm, we could not find a significant difference between the groups in terms of CSS rates. This outcome was similar to the outcomes of the above-mentioned studies. An important reason for the similar long-term CSS rates may be that practitioners perform immediate complementary nephrectomy when local recurrence is detected. In our opinion, prospective-randomized studies are needed to understand the real effect of the SMW on CSS rates.
If a PSM is present in the final histopathological examination, the available further treatment options are controversial. Most clinicians prefer complementary radical nephrectomy or resection of the surgical margin in this case; however, there is a risk of not being able to find the tumor in the resected specimen. Sundaram et al. performed complementary nephrectomy in 8 of 29 patients with PSMs and resection of the surgical margin in 21, and they detected tumors in none of the nephrectomy cases and in only two of the re-resected margins. The authors concluded that repeat surgical treatment is an overtreatment in the case of PSMs. Among the studies evaluating the effect of a PSM during the follow-up period, Kwon et al. and Khalifeh et al. reported 4% and 9.5% of recurrence and metastasis rates, respectively. In the nonsystematic review of Marszalek et al., it was emphasized that patients with PSMs could be managed with monitoring rather than surgical treatment. On the other hand, in the multicenter studies of Khalifeh et al., the presence of PSMs was associated with an increased risk of local recurrence and metastasis. For this reason, a PSM is a condition that must be meticulously focused on. In our study, the rate of local recurrence in cases with PSMs was higher than in previous studies (33%); however, survival rates were similar to cases with NSMs due to the close follow-up of cases and immediate application of radical nephrectomy in cases with recurrence.
Providing a 10-mm surgical margin during NSS has historically been accepted. However, this information is questioned because similar recurrence rates have been provided with shorter surgical margins. In a study of 126 patients who had NSMs with NSS, the resection margins were less than 1 mm in all nine patients with local recurrence, and no recurrence was found in any of the 49 patients whose margins were longer than 1 mm; however, recurrence did not affect the overall survival and CSS rates. There are some rational reasons for recurrence in the presence of NSMs. For example, a new primary tumor may develop or the recurrence may be due to a malignancy that cannot be diagnosed in the resection area, both of which leads to a false-negative evaluation of the surgical margin. Another possibility may be that small tumor areas are located outside of the focused tumor site during surgery. Chen et al. have shed light on this issue and showed that 39% of T1b renal tumors have focal tumor areas that extend 3 mm beyond the tumor pseudocapsule. In light of such data, it would not be wrong to say that the resection of entire tumor, which is noticed during surgery, is more important than the SMW.
This study has some limitations. This is a retrospective study of a single center. For this reason, selection bias may have affected the results. Application of immediate complementary nephrectomy for patients with local recurrence may have masked the true effect of PSMs in these patients.
| Conclusion|| |
PSMs and SMWs provided during NSS have negative effects on local recurrence rate, but not on the CSS rate, of patients with RCC. Tumor diameter, enucleation, and <2 mm SMW are important factors affecting local recurrence. Complete removal of the tumor during NSS appears to be more effective than SMWs for improving survival rates. These results need to be verified with prospective, long-term follow-up studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]