External histopathological validation of the surface-intermediate-base margin score

Urologic Oncology: Seminars and Original Investigations 35 (2017) 215–220

Original article

External histopathological validation of the surface-intermediate-base margin score Alessandro Antonelli, M.D.a, Maria Furlan, M.D.a,*, Mario Sodano, M.D.a, Francesca Carobbio, M.D.a, Regina Tardanico, M.D.b, Simona Fisogni, M.D.b, Claudio Simeone, M.D.a a

Department of Urology, Spedali Civili Hospital, University of Brescia, Brescia, Italy b Pathology, Spedali Civili Hospital, University of Brescia, Brescia, Italy

Received 4 July 2016; received in revised form 6 December 2016; accepted 19 December 2016

Abstract Purpose: The surface, intermediate, and basis (SIB) is a system based on surgeon's visual assessment of the thickness of healthy parenchyma remaining on the intrarenal portion of the tumor. This system has been proposed to standardize the nomenclature of the resection technique (RT) during partial nephrectomy (PN). Our study aims at evaluating whether the SIB score visually assigned is related to the thickness of parenchyma measured by microscopy. Materials and methods: Data of 52 patients submitted to PN from April to October 2015 were perspectively collected. All the excisions were performed following a “nonanatomical” strategy according to our institutional intention to resect the tumor with a visible margin of parenchyma. After the removal of the specimen, 2 trained examiners applied the SIB system: the intrarenal portion of the nodule was ideally divided into 3 circumferential sectors (surface, intermediate, and basis); on each of these was identified the area covered by the lowest amount of parenchyma (score specific area [SSA]); and a score descriptive of the thickness of parenchyma was assigned to each area. The RT performed (enucleation, enucleoresection, or wedge resection) was defined by the sum of the scores. The same examiners inked every SSAs with a different color and then dedicated pathologists, blinded of the scores assigned, and microscopically measured the parenchyma covering each SSA. The relationship between these values and the SIB scores was assessed. Results: According to the SIB nomenclature, the technique performed was enucleation for 31 patients (60%), enucleoresection for 16 (31%), and wedge resection for 5 (9%). For the surface SSA, the median/mean values of the thickness for S ¼ 0 vs. S ¼ 1 was 0.35/0.84 vs. 2.00/2.26 mm and for the intermediate or base SSA, the median/mean value of the thickness for S ¼ 0 vs. 1 vs. 2 was 0.35/0.47 vs. 1.00/ 1.50 vs. 2.00.5/2.33 mm. All the comparison reached statistical significance. Conclusions: The visual description of the surgical plane followed during PN according to the SIB system is related to the microscopic thickness of healthy parenchyma covering the tumor. The SIB system can correctly discriminate among different R techniques, and therefore could be a crucial tool to standardize the nomenclature of PN. r 2017 Elsevier Inc. All rights reserved.

Keywords: Renal cell carcinoma; Partial nephrectomy; Kidney neoplasm; Nephron-sparing surgery

1. Introduction When technically feasible, partial nephrectomy (PN) is preferred over radical nephrectomy for all cT1 renal tumors, because it offers equal cancer-specific survival but longer overall survival [1–5]. Clearly, even if organ-sparing, PN must be adherent to the principles of oncological radicality. Corresponding author. Tel.: þ39-030-399-5217. E-mail address: [email protected] (M. Furlan). *

http://dx.doi.org/10.1016/j.urolonc.2016.12.011 1078-1439/r 2017 Elsevier Inc. All rights reserved.

Historically, to achieve this goal the removal of a macroscopical margin of healthy parenchyma through a wedge resection WR was advocated as necessary. However, in more recent years, a large amount of data have showed that an excision around the tumor contour keeping a smaller margin of a few millimeters is equally adequate, so this technique— enucleoresection (ER)—has become the gold standard [6,7]. Some institutions further emphasized this trend toward the progressive reduction of the width of the margin, turning to a pure enucleation (E) that removes just the “minimal” layer of

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tissue adherent to the pseudocapsule [8]. Thus, briefly, 2 possible strategies can be planned before PN: the first is “anatomic” when the surgeon follows the tumor-parenchyma interface with the intention to perform an E; the second is “non-anatomic” when the dissection goes through the parenchyma far from the tumor margins with the intention to perform an ER or a WR [9]. The implications of the resection technique (RT) on surgical morbidity, preservation of renal function, and oncological safety have been widely debated in the literature, with a general agreement on the equivalence of the different strategies [10–16]. Nevertheless, it is underestimated that all these studies rely just on the institutional intentions rather than on a caseby-case analysis of the RT effectively performed, merely assumed to be consistent with the declared intentions. Conversely, the procedure can differ from the intentions of the surgeon, due to the incompleteness or penetration of the pseudocapsule [17] or nephrosclerosis [18] or difference in histologic subtype [19]. Morevover the approach can change from the surface of the nodule, where the borders are easily recognizable, to its basis where they must be realized and the vascular and excretory structures need to be preserved [20]. However, almost all of the published series are heterogeneous, composed by a mixture of surgical procedures, and this discrepancy between the reported vs the truly performed RT represents a huge bias in the literature on this topic. The surface-intermediate-base (SIB) score has been recently proposed by Minervini and Kutikov [21] to standardize the nomenclature of the PN techniques. Briefly, the first step is the identification of 3 circumferential sectors in the nodule, the more superficial (surface, S), the intermediate (intermediate, I), and the deeper one (basis, B); then, the area with the minimum thickness of parenchyma (score specific area [SSA]) is individuated on each of these sectors and a score is assigned by the visual assessment of the amount of normal tissue covering the SSA; and finally, the sum of the scores defines the procedure effectively done. The first requirement the system should satisfy is that the human eye, driven by the rules of the system, is able to discriminate between different thicknesses of parenchyma. This issue has recently been investigated by Minervini et al. [22] in a so-called “histopathological validation” of their system, showing a good correlation between the scores and the width of the parenchyma removed. However, this study suffers from a few limitations related to the poor heterogeneity of the cohort, composed by cases all submitted to robotic PN after an “anatomical” RT. Therefore, the conclusions reached may not be applied to cohorts treated with an open PN or a “nonanatomical” surgical strategy. The present study aims at providing a further histopathological validation of the SIB score, but in a cohort of patients treated at an institution that follows a nonanatomical strategy, to assess the reproducibility of the system also in this specific setting.

2. Materials and methods Since the 1980s, our institution followed a “nonanatomical” strategy in the approach to PN by dissecting the tumor on a safety margin of normal parenchyma, with an aim to perform an ER as the final procedure. From a technical point of view, after a circumferential sharp incision of the renal capsule done a few millimeters far from the borders of the tumor, a mixed sharp and blunt dissection is done maintaining a few millimeters of healthy parenchyma on the tumor. After institutional review board approval, the data of 52 consecutive patients submitted to PN between April and October 2015 were prospectively collected. The surgical procedures were done by 6 experienced surgeons (1 for robotic surgery and 5 for open PN) through an extraperitoneal lumbotomic or robot-assisted transperitoneal or retroperitoneal access, according to the patient's features or surgeon's preferences; however, in every case, the renal artery was isolated but clamped during the excision depending on tumor features and surgeon preference. 2.1. SIB score assignment For the present study, 2 examiners (M.S. and M.F.), after a short education consisting in the reading and critical discussion of the dedicated literature, assigned the SIB score still in the operating theater, orienting the specimen with the help of the surgeon; a senior author (A.A.) was consulted to solve any disagreement. After the methodology suggested by Minervini et al. [21], the intrarenal portion of the tumor was divided into 3 equal circumferential macroareas (surface, S; intermediate, I; and base, B) and within each of them the area covered by the minimum thickness of parenchyma, defined as SSA, was identified (Fig. 1). Then, a score was given according to the definitions reported by Table 1 to describe the amount of healthy renal tissue on each SSA. Finally, the RT effectively performed was defined by the sum of the scores, according to the following intervals: 0 to 1—pure E; 2—hybrid E; 3—pure ER; 4—hybrid ER; and 5—WR. 2.2. Specimen preparation and measurement of healthy parenchyma on SSAs The 2 examiners inked the SSA that they had previously identified with different colors (basis SSA—black ink, intermediate SSA—green ink, and surface SSA—blue ink), after a preliminary dunking of the tumor in acetic acid 60% to stabilize the ink, and then fixed the specimen in a 10% formalin solution. Two dedicated uropathologists (R.T. and S.F.) were preliminarily informed on the features of the SIB system and involved in the design of the study, so that a pathological protocol was defined. The pathologists remained blinded of the assignment of the SIB by the surgeon until the completion of the analysis of all the patients. According to the protocol, a section of the central portion of each inked SSA was taken and the thickness of

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Fig. 1. Speciment preparation for SIB score assignment to the score specific areas (SSA) and microscopical view of the SSA, an example of SIB score 1 þ 1 þ 2. (Color version of figure is available online.)

the healthy renal parenchyma over the profile of the tumor was measured by a millimeter lens at 5 magnification, taking at least 10 independent measures for each SSA. Considering that the irregularity of the profile of the SSA, to be as much descriptive as possible, were recorded the maximum, the minimum, and the most represented (i.e., the mode of measurements) value of thickness (Fig. 2). Finally, the tumor was examined according to the International Society of Urological Pathology Vancouver classification [23,24]. The TNM classification followed the 2010 version [25]. The events of complications were systematically recorded and graded according to the Clavien-Dindo system [26]. The surgical outcome was defined by the margin ischemia complication system [27] according to which a favorable surgical outcome is achieved only if 3 conditions —negative surgical margins, ischemia time less than 20 minutes, and no grade 3 to 4 complications—are simultaneously satisfied.

2.3. Statistical analysis The outcome variables were maximum, minimum, and most represented thickness for each SSA; however, the relationship between the outcomes and the scores for the surface SSA (S ¼ 0 or 1) was analyzed independently, whereas the scores of the intermediate and basis SSA were analyzed joined (I or B ¼ 0, 1, or 2), given the different definitions of E, ER, and WR between S and I/B areas (Table 1). Continuous variables were presented as mean/ standard deviation and median/interquartile range: 25 to 75, categorical variables as the absolute number and frequency. The correlation between variables was estimated by Student t-test or analysis of variance, Mann-Whitney U or the Kruskall-Wallis tests as appropriate. All tests were 2-sided and were considered significant for a P o 0.05. All the statistics were computed by SPSS v.20.

3. Results Table 1 Methodology for the SIB score assignment on each SSA Resection technique Visual definition in the SSA Enucleation

Enucleoresection

Wedge resection

Surface Intermediate Base

Only the 0 pseudocapsule is visible without additional tissue A minimal margin of 1 additional tissue is present, but the tumor contour is still visible A margin of healthy 1 tissue is present and the tumor contour is not visible

0

0

1

1

2

2

Table 2 reports the general features of the cohort. Table 3 shows the results of the score assignment, the sum of scores and the consequent definition RT according to the SIB nomenclature: in 31 patients (59.6%) was performed an E— pure (22) or hybrid (9), in 16 (30.8%) an ER—pure (9) or hybrid (7), and in 5 (9.6%) an WR. Among these 3 groups, no differences were found in tumor diameter (E vs. ER vs. WR, 3.6 vs. 3.0 vs. 3.4 cm, respectively, P ¼ 0.561), RENAL score (7 vs. 7 vs. 8, P ¼ 0.298), positive surgical margin rate (9.7% vs. 6.3% vs. 0.0%, P ¼ 0.728), and margin ischemia complication achievement (77.4% vs. 93.8% vs. 80.0%, P ¼ 0.369); conversely, there was a significant difference in the use of the robotic technique (32.3% vs. 68.8% vs. 40.0%, P ¼ 0.049) and clamping of the artery (38.7% vs. 81.3% vs. 80.0%, P ¼ 0.011).

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Fig. 2. Microscopical measures of the thickness of parenchyma around the endophytic portion of the tumor correlated with the score visually assigned by the surgeon.

The evaluation of the thickness of healthy parenchyma in the SSA provided the results shown in Fig. 2. For all the comparisons, overall and pairwise, and referring to the minimum, maximum, and most represented values, a statistically significant difference (all P o 0.05) was found.

4. Discussion This study finds a significant relationship between the scores suggested by the SIB system and the thickness of normal parenchyma covering the 3 sectors in which the intrarenal portion of the nodule is subdivided. These results reveal that, adopting the definitions suggested by this system, the human eye has the ability to significantly discriminate different amounts of tissue. Such a discrimination is indicative of the surgical plan followed during the excision—the tumoral pseudocapsule, a minimal, or larger layer of healthy parenchyma—and therefore, correctly describes the surgical technique performed: E, ER, or WR. The system proved also to be easy to use, just after a simple training. Regarding convenience and time demanding such a system overcomes other ways to describe the RT, as a bivalve section of the nodule to measure radial margins along the endophytic portion, because it does not require any manipulation of the tumor or adjunctive instrumentations, such as lenses or microscopes. It is possible to declare that the SIB system is reproducible. Hence, accounting for the differences in the RT, the values of the parenchymal thickness were found very similar to the ones reported by Minervini et al. [22] indicating that the definitions of E, ER, and WR have been univocally

applied by the examiners. Regarding the surface sector, the concordance in the values assigned for S ¼ 0 was almost complete (median value of the maximum thickness 0.35 mm in the present study vs. 0.20 mm), whereas there was a difference for S ¼ 1 (2.00 mm vs. 0.97 mm) attributable to the different approaches of the 2 institutions: in case of a “non-anatomical” approach—like ours—in the category S ¼ 1 wider excisions are included, whereas in case of an “anatomical” approach the dissection starts closer to the tumor. Comparable values were found for the intermediate/ base sectors, for the score 0 (0.35 vs. 0.24 mm), 1 (1.00 vs. 0.88 mm), and 2 (2.00 vs. 2.95 mm). As in the study of Minervini [22] and also in the present one, it was confirmed that a statistically significative difference in the pairwise comparison of values among different scores, indicating that the visual appearance of the surface of the nodule correlates with the plan developed during the dissection. These considerations support the adoption of a nomenclature of PN that takes into account 3 distinct techniques (E, ER, and WR) and can contribute to the ongoing debate on this issue [28]. Including a wider range of RTs, the present study provided information on the discriminative ability of the SIB system even for the institutions that adhere to a nonanatomical resective strategy, which are probably more [29]. Most of all, for the first time, the data of SIB scores of “anatomical” and “nonanatomical” institutions are available raising a major criticism on the already published literature dealing with the comparison of these 2 options. Hence, in most cases, the in-depth evaluation of the surgical specimen led to the reclassification of the RT effectively performed regarding preoperative presumed intentions: in the study of

A. Antonelli et al. / Urologic Oncology: Seminars and Original Investigations 35 (2017) 215–220 Table 2 General features of the cohort Feature Gender Male Female Age, y (mean, standard deviation) Serum creatinine, mg/dl (mean, standard deviation) Charlson comorbidity index 0 1 41 Clinical diameter, cm (median, IQR) RENAL score, median (min, max) Indication Elective Imperative Surgical approach Open Robotic Ischemia No Warm Cold Ischemia time, min (median, IQR) Histological subtype Benign Clear cell Papillary Chromophobe Other Pathological diameter, cm (median, IQR) Extracapsular invasion Positive surgical margin MIC score achievement

Value 35 (67.3%) 17 (32.7%) 59.8 ⫾ 10.4 0.92 ⫾ 0.37 33 8 11 3.0 7

(63.5%) (15.4%) (21.1%) (2.4–4.2) (4–10)

48 (92.3%) 4 (7.7%) 29 (55.8%) 23 (44.2%) 23 27 2 14

(44.2%) (51.9%) (3.8%) (10–18)

10 23 9 8 2 3.0 1 4 43

(19.2%) (44.2%) (17.3%) (15.4%) (3.8%) (2.3–4.2) (1.9%) (7.7%) (82.7%)

IQR ¼ interquartile range 25 to 75; MIC ¼ margin ischemia complications.

Minervini [22] 30% of the cases were not an E and viceversa in our experience 60% were not submitted to a resective procedure. Finally, it is noteworthy that the considerable rate of cases (30%) submitted to a hybrid technique in which the plan of excision changed during the dissection, confirming that a “pure” RT is often solely claimed. This study, with respect to the original one, benefits from a more heterogeneous cohort that included open and robotic PN; clamp and off-clamp PN, both in a 1:1 ratio; providing information on the relationship between the RT; classified according to the SIB score; and the surgical outcomes. There was a significantly lower rate of E among the cases submitted to robotic PN, indicating that in the lack of a tactile feedback the dissection is done farther from the tumor, at least at our institution. Artery clamping was more frequent in the patients submitted to ER or WR, as expected, considering that bleeding is surely more prominent than during an E. No differences were found between the RT and the preoperative features of the tumor suggesting that surgical strategy is generally established only during the operation.

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Table 3 Results of the assignment of scores and definition of the resection technique S

I

B

Sum

No.

Resection technique

No. (%)

0 0 0 1 0 0 1 1 0 1 0 1 1 1 1

0 0 1 0 0 1 0 1 1 1 2 1 1 2 2

0 1 0 0 2 1 1 0 2 1 2 2 2 1 2

0 1

12 4 2 4 1 4 2 2 5 4 1 3 1 2 5

Pure SE

22 (42.3%)

2

3 4

5

Hybrid SE

9 (17.3%)

Pure ER

9 (17.3%)

Hybrid ER

7 (13.5%)

WR

5 (9.6%)

SE ¼ simple enucleation; WR ¼ wedge resection.

Finally, no statistical differences were found in the rate of positive surgical margins. However, among the cases submitted to E this rate was trending higher, and probably clinically if not statistically relevant. This poses some concerns on the risk portended by a dissection so close to the tumor, especially at institutions not prone to this strategy. This study is not devoid of limitations that include the small size of the cohort and the lack of a sample size calculated a priori. Other limitations inherent to the SIB system have not been solved or just mitigated by this study: the assumption that the SSA is the most representative portion of its whole macroarea; the intraobsever and interobserver variability in the identification of the SSA, that we attempted to reduce inking the SSAs before to refer the specimen to the pathologist; the interobserver variability of the assignment of the SIB score; the real clinical usage of the inclusion of hybrid techniques that probably could be grouped with their pure counterparts, as we did for the assessment of the relationships with surgical outcomes; and the lack of information on the intention of the surgeon in each specific case to correlate case-by-case the surgical planning with technique effectively performed.

5. Conclusions The visual assignement of the SIB score significantly correlates with the histopathological measures of the healthy parenchyma margin around the endophytic portion of tumor on the SSA, even in case of various excision strategies and surgical techniques. The reproducibility and ease of this system support its adoption to improve the nomenclature of PN and the quality of the literature on this topic.

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