World J Urol (2013) 31:835–839 DOI 10.1007/s00345-011-0720-1
ORIGINAL ARTICLE
Pathologic evaluation of non-neoplastic renal parenchyma in partial nephrectomy specimens Michael Garcia-Roig • Michael A. Gorin • Carlos Parra-Herran • Monica Garcia-Buitrago • Bruce R. Kava • Merce Jorda • Mark S. Soloway Murugesan Manoharan • Gaetano Ciancio
•
Received: 28 March 2011 / Accepted: 8 June 2011 / Published online: 21 June 2011 Ó Springer-Verlag 2011
Abstract Purpose This study aimed to identify non-neoplastic pathologic changes in partial nephrectomy specimens of patients without a known history of medical comorbidities. Routine analysis of this tissue may allow the clinician to identify subclinical renal disease. Methods We retrospectively reviewed our database of patients who underwent open partial nephrectomy for a small renal mass. Non-neoplastic tissue of partial nephrectomy specimens of patients without a known history of chronic kidney disease, diabetes mellitus, hypertension, or coronary artery disease was evaluated for glomerular, interstitial, and vascular pathologic changes. Results A rim of non-neoplastic tissue was adequate for pathologic evaluation in 91.8% of specimens. A total of 45 patients were studied with a median age of 52.0 years. Atherosclerosis was the most commonly identified pathologic finding in 9 (20%) patients, followed by mesangial expansion and interstitial fibrosis, each found in 8 (17.8%) patients. Linear regression found interstitial fibrosis to be the only pathologic lesion associated with preoperative
M. Garcia-Roig M. A. Gorin B. R. Kava M. S. Soloway M. Manoharan G. Ciancio Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA C. Parra-Herran M. Garcia-Buitrago M. Jorda Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA G. Ciancio (&) Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine, Post Office Box 012440, Miami, FL 33101, USA e-mail:
[email protected]
serum creatinine (coefficient = 0.697, P = 0.001). Male gender was also associated with a higher preoperative creatinine (coefficient = 0.270, P = 0.034). Postoperative serum creatinine was not associated with any of the examined lesions. Conclusions Current surgical techniques provide adequate non-neoplastic tissue for pathologic evaluation. We observed a striking degree of pathologic disease in patients without a known history of medical comorbidities. Routine inspection of the non-neoplastic parenchyma of partial nephrectomy specimens should be performed as it can alert the clinician to presence subclinical renal disease allowing for medical intervention. Keywords Partial nephrectomy Pathologic evaluation Renal function
Introduction Concurrent with improvements in cross-sectional imaging, the incidence of small renal masses (SRMs) has greatly increased in the last several decades with average age at diagnosis now in the early 60’s [1, 2]. Guidelines from the American Urological Association [3] and European Association of Urology [4] favor partial nephrectomy (PN) for the management of SRMs, as radical nephrectomy has been associated with chronic renal insufficiency and decreased survival. Sparing non-neoplastic renal tissue maintains long-term renal function in an aging population with medical comorbidities [5–7]. Current protocol from the College of American Pathologists recommends the regular inspection of nonneoplastic parenchyma in nephrectomy specimens [8]. Pathologic changes in this tissue may provide evidence of
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preexisting and potentially progressive renal and systemic disease. Despite this recommendation, data are limited to support the routine evaluation of the normal parenchyma of PN specimens [9, 10]. A negative surgical margin at the time of PN confirms local cancer control and concomitantly provides tissue that can be assessed for non-neoplastic pathologic changes. The objective of this work was to describe the pathologic changes found in the negative margin of partial nephrectomy specimens among patients with no known history of comorbid medical disease. We hypothesize that this tissue may have therapeutic significance since it can alert the clinician to the presence of subclinical renal disease.
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Statistical analysis Data were tabulated and analyzed using SPSS 18.0 (IBM, Somers, NY). A multivariate linear regression was performed to determine independent factors associated with pre- and post-operative renal function. A P value of B0.05 was considered statistically significant. The following parameters were included as covariants of these analyses: presence/absence of the studied non-neoplastic pathologic findings (excluding arteriolosclerosis), tumor size, patient age, and gender. In addition, preoperative creatinine, renal artery clamp time, and use of ice were included in the regression for postoperative renal function.
Results Materials and methods Clinical data collection We reviewed our Institutional Review Board-approved retrospective database of open partial nephrectomy cases performed by three urologic oncologists at our institution. Previously, we have reported on our PN experience with this database [11]. Patients were excluded for a known history of diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, and prior contralateral nephrectomy. Parameters queried included age, sex, race, tumor characteristics, preoperative blood pressure, preoperative dipstick urine protein, preoperative serum creatinine (within 1 year of surgery), and postoperative creatinine (3–12 months following surgery). When multiple creatinine values were available, the value closest to the date of surgery was used. Pathologic evaluation Non-neoplastic renal parenchyma was evaluated for segmental lesions, mesangial expansion, focal glomerular basement membrane (GBM) thickening, interstitial fibrosis, atherosclerosis, and arteriolosclerosis. Segmental lesions, mesangial expansion, and focal GBM thickening were recorded as either present or absent. Interstitial fibrosis, atherosclerosis, and arteriolosclerosis were considered significant if found in [25% of tissue. Peritumoral parenchyma (1 mm) was not examined. Tissue distal to the tumor margin was always evaluated so as to avoid the local effects of the tumor on immediately adjacent tissue. Specimens were only included in the analysis if there existed peri-tumoral parenchyma larger than 1 mm in width, and if 10 or more glomeruli were present in the specimen for examination.
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Between September 1993 and March 2009, 182 patients underwent open PN by three urologic oncologists at our institution for renal masses less than 7 cm (i.e., T1a and T1b). Of these patients, 68 had no known history of diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, or prior contralateral nephrectomy. Tissue blocks for pathologic analysis were available for 49 of these cases. A rim of non-neoplastic tissue was adequate for pathologic analysis in 45 samples (91.8%). The median age at the time of PN was 52.0 years. Males comprised 60% of this group. Median tumor size was 3.0 cm, and tumor histology included 35 (77.8%) patients with renal cell carcinoma. Baseline demographics and tumor characteristics are detailed in Table 1. Non-neoplastic pathologic changes suggestive of progressive renal disease were identified in 19 of 45 patients (42.2%). Pathologic findings are detailed in Table 2. Moderate atherosclerosis was the most common non-neoplastic lesion identified in 9 (20%) patients. In contrast, arteriolosclerosis was not found in any patient. Mesangial expansion and interstitial fibrosis were the next most common, each found in 8 (17.8%) specimens, with one case of interstitial fibrosis being severe. Focal segmental lesions and GBM thickening were present in and 3 (6.7%) and 2 (4.4%) patients, respectively. Figure 1 demonstrates pathologic findings found in three patients without a known history of medical disease. Among the 19 patients with pathologic changes, 2 (10.5%) had a positive urine dipstick for protein. Both had interstitial fibrosis as their only pathologic finding. A linear regression demonstrated that interstitial fibrosis was independently associated with preoperative serum creatinine (coefficient = 0.697, P = 0.001, Table 3). An association with gender was also noted, with males having a higher preoperative creatinine (coefficient = 0.270, P = 0.034). All other pathologic findings studied failed to demonstrate an association with preoperative creatinine.
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Discussion
Table 1 Study cohort characteristics Characteristic
n = 45
Age (years), median (IQR)
52.0 (42.9–63.3)
Sex, n (%) Male
27 (60.0)
Female
18 (40.0)
Race, n (%) White
45 (100)
Black
0 (0)
Preoperative, median (IQR) Serum Cr (mg/dl)
1.0 (0.84–1.10)
Systolic BP (mmHg)
130 (121–140)
Diastolic BP (mmHg) Postoperative, median (IQR) Serum Cr (mg/dl)
80 (70–90) 1.1 (0.9–1.3)
Tumor Size (cm), median (IQR)
3.0 (3.0–4.0)
Benign, n (%)
20 (22.2)
Angiomyolipoma
5 (11.1)
Oncocytoma
3 (6.7)
Benign cyst
1 (2.2)
Hemangioma
1 (2.2)
Malignant, n (%)
35 (77.8)
Clear cell
29 (64.4)
Papillary RCC
4 (8.9)
Chromophobe RCC
2 (4.4)
BP blood pressure, Cr creatinine, IQR interquartile range, RCC renal cell carcinoma Table 2 Pathologic changes observed in the non-neoplastic parenchyma of partial nephrectomy specimens Pathologic finding
n (%)
None
26 (57.8)
Segmental lesions
3 (6.7)
Mesangial expansion
8 (17.8)
Focal GBM thickening
2 (4.4)
Interstitial fibrosis
8 (17.8)
Moderate Severe Atherosclerosis Moderate Severe Arteriolosclerosis
7 (15.5) 1 (2.2) 9 (20.0) 9 (20.0) 0 (0.0) 0 (0.0)
Moderate
0 (0.0)
Severe
0 (0.0)
GBM glomerular basement membrane
Linear regression analysis failed to demonstrate that any of the studied pathologic findings were associated with postoperative serum creatinine.
Partial nephrectomy for the management of SRMs provides effective cancer control and preserves renal function [3, 4]. We hypothesize that the renal parenchyma removed around the tumor can be used to improve patient survival beyond cancer control and renal function. We believe that pathologic evaluation of the peritumoral renal parenchyma may provide insight into the status of the remaining renal tissue allowing for appropriate medical intervention. In our series, non-neoplastic tissue was adequate for pathologic evaluation in 91.8% of specimens. We excluded tissue with less than 10 glomeruli or only renal medullary tissue for evaluation. We noted uniform pathologic abnormalities in the non-neoplastic tissue of those patients studied. Also, we did not note clusters or a gradient of pathologic findings leading up to the tumor. This finding suggests that the standard rim of normal tissue taken at the time of partial nephrectomy is adequate for pathologic evaluation in almost all cases. It has been shown that the amount of peritumoral renal parenchyma taken with PN does not correlate with cancer control as long as the margin is truly negative [12]. Piper et al. [13] studied 49 patients with a 1-cm peritumoral margin and found no recurrence at 73 months in all patients. With cancer control being the primary goal of PN for renal cancer, a negative margin should be attained in a standard fashion. We do not recommend an extended surgical margin for renal parenchyma evaluation as this undermines the goal of preserving renal function. In our experience, we found that a standard surgical margin allowed for pathologic analysis of the in situ kidney in [90% of cases. Our results show that patients with no prior diagnosis of medical renal disease can have significant pathologic changes in the non-neoplastic tissue obtained at the time of PN. Patients with no known history of comorbid medical diseases (i.e., diabetes, hypertension and coronary artery disease) had significant pathologic findings in 42.2% of specimens. This data suggest that a significant proportion of patients undergoing PN have undiagnosed and/or subclinical progressive renal disease. Arteriolosclerosis, mesangial expansion, and interstitial fibrosis were the most common lesions observed (Table 2). Linear regression analysis demonstrated interstitial fibrosis to be associated with a higher preoperative creatinine (coefficient = 0.697, P = 0.001, Table 3). This finding is in agreement with mechanisms of progressive glomerular injury including interstitial fibrosis and focal segmental glomerulosclerosis [14, 15]. None of the studied pathologic features were associated with postoperative renal function. Current guidelines from the College of American Pathologists recommend the routine study of non-
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Fig. 1 Representative non-neoplastic pathologic changes from patients without known medical comorbidies (a) Glomerulus with segmental mesangial expansion and hypercellularity (arrow). Hematoxilin Eosin,
9400 (b) Renal interstitial fibrosis and tubular atrophy. Hematoxilin Eosin, 9200 (c) Moderate atherosclerosis involving approximately 50% of the lumen (arrow). Hematoxilin Eosin, 9100
Table 3 Linear regression to determine predictors of preoperative serum creatinine
While this study supports the pathologic evaluation PN specimens for evidence of non-neoplastic disease, there are limitations to this work. The most major limitation is its retrospective design that may have introduced an information bias to our results. A more robust study design would include prospective collection of data with corroboration of patient-provided medical history. A second limitation is sample size. While a large percentage of patients without a known history of medical disease were found to have pathologic changes, it is difficult to generalize these results on the basis of 45 patients. Future work aims to explore clinical outcomes of patients for whom non-neoplastic findings were prospectively reported. This study design will better assess the true clinical utility of routine evaluation of non-neoplastic parenchyma of PN specimens.
Predictor
Coefficient
Age
-0.006
0.226
0.008
0.958
Atherosclerosis Focal GBM thickening Gender Interstitial fibrosis
P value
-0.193
0.640
0.270
0.034
0.697
0.001
Mesangial expansion
-0.234
0.226
Segmental lesions Tumor size
-0.258 -0.008
0.463 0.801
GBM glomerular basement membrane
Males were more likely to have elevated creatinine
neoplastic renal parenchyma in nephrectomy specimens [8]. In contrast, protocol from the Association of Directors of Anatomic and Surgical Pathology do not include this requirement [16]. This is perhaps related to the paucity of data on the utility of evaluating non-neoplastic disease [9, 10]. This is especially true for PN specimens. Additionally, this may be in part due to the lack of formal training in medical renal pathology by up to 30% of pathology training programs in the United States [10]. Our results support the evaluation of this tissue. We believe that routine reporting of non-neoplastic findings may result in further improved overall clinical outcomes for these patients. For example, vascular lesions such as atherosclerosis and arteriolosclerosis indicate systemic diseases for which medical therapy is readily available. Treatments include lifestyle modification and medications such as statins and other lipid lowering agents. Similarly, interstitial fibrosis is a disease specific to the kidney where treatment options to control progression exist in the hands of the appropriate specialist. Inhibition of the reninangiotensin system has been shown in humans and animals to prevent progression of fibrosis [17, 18].
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Conclusions Current PN technique provides adequate tissue for evaluation of non-neoplastic renal parenchyma. Our findings suggest that pathologic evaluation of the negative margin of PN specimens can shed light on subclinical comorbid disease in patients who otherwise have no medical diagnosis. The presence of clinically significant lesions on pathology should prompt investigation by the appropriate medical specialist to protect remaining renal function. Conflict of interest
None.
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