Renal Cell Carcinoma: Histological Findings on Surgical Margins After Nephron Sparing Surgery

0022-5347/03/1693-0905/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 169, 905–908, March 2003 Printed in U.S.A.

DOI: 10.1097/01.ju.0000046779.58281.c4

RENAL CELL CARCINOMA: HISTOLOGICAL FINDINGS ON SURGICAL MARGINS AFTER NEPHRON SPARING SURGERY A. ZUCCHI, L. MEARINI, E. MEARINI, E. COSTANTINI, C. VIVACQUA

AND

M. PORENA

From the Urology Department, University of Perugia, Perugia, Italy

ABSTRACT

Purpose: We evaluated the incidence of peritumoral satellite lesions in nephron sparing surgery and examined whether these findings have a negative effect on cancer specific survival and on the percent of local recurrence. Materials and Methods: We performed nephron sparing surgery in 63 patients with kidney cancer, including 53 elective (group 1) and 10 imperative (group 2) operations. In all cases we removed 10 mm. of apparently healthy peritumoral parenchyma with the tumor. This tissue was subsequently examined by an anatomical pathologist to identify any satellite lesions. Results: Four satellite lesions were identified, including 3 in group 1 and 1 in group 2, at a mean of 5.3 mm. from the primary lesion. None of the patients in either group had local recurrence at followup. Cancer specific survival was 96.3% in group 1 (mean followup 61 months) and 58% in group 2 (mean followup 39 months). It was not influenced by the presence of satellite micro-lesions. Conclusions: Despite common perplexities concerning the risk of multifocality in renal cell carcinoma we believe that the nephron sparing procedure in select patients is as effective as radical surgery. Based on our experience the surgical safety margin must be at least 10 mm. of macroscopically healthy, peritumoral tissue. KEY WORDS: kidney; carcinoma, renal cell; neoplasms, multiple primary

Radical nephrectomy, which may or may not be associated with lymph node dissection, continues to be the treatment of choice for renal cell carcinoma despite the good results recently achieved with NNS.1 Imperative conservative surgery (bilateral tumors, patients with 1 kidney and so forth) has always received unanimous consent, justified by the overall 5-year survival rate of 84% to 88% and a 9% to 10% rate of local recurrence.1 Elective conservative surgery continues to be controversial, although several recently published studies show survival rates similar to those obtained with radical surgery for low stage, low grade lesions that are less than 4 cm.1 As shown in the recent literature, nephron sparing surgery has a positive impact on preserving renal function, in contrast to radical nephrectomy.2, 3 A frequent controversy and one that has recently become the focus of attention after the introduction of laparoscopy for treating kidney tumors involves the choice of enucleationresection and partial resection. This debate has been fueled by controversies over the possible multifocal nature of renal cell carcinoma. In 1990 we performed a prospective study to evaluate peritumoral tissue in patients who underwent imperative and elective nephron sparing surgery, evaluating the incidence of multifocal satellite lesions in peritumoral tissue.4 We also evaluated recurrence-free survival in these patients at a mean followup of 61 months. MATERIALS AND METHODS

Since 1990, we have performed 63 nephron sparing operations for renal cell carcinoma. All patients underwent preoperative staging, including renal ultrasound, abdominal computerized tomography (CT), selective renal arteriography, chest x-ray and bone scan. The most recent 15 cases were also examined via spiral CT. All tumors were staged according to the 1997 TNM system as T1N0M0. The tumors were localAccepted for publication October 4, 2002.

ized in the superior pole in 27% of cases, mid portion of the kidney in 43% and the lower pole in 30%. Patients were divided into groups 1— elective and 2—imperative conservative surgery. Group 1 included 43 males and 10 females 18 to 79 years old (mean age 56.8 years). Preoperatively tumors were less than 3 cm. in 39 cases (73%). All tumors were localized to a peripheral site. Group 2 included 4 males and 3 females 58 to 74 years old (mean age 65 years). Conservative surgery was imperative in 3 cases due to a single kidney in 1, bilateral involvement in 3 and cancer of the contralateral upper urinary tract (renal pelvic transitional cell carcinoma) in 1.

SURGICAL TECHNIQUE

The surgical technique was the same in all cases via the retroperitoneal approach. Gerota’s fascia was incised to expose the kidney, leaving in situ only the fatty tissue next to the cancer. The whole kidney surface was inspected for any multifocal lesions that were not identified by previous diagnostic examinations. We did not routinely perform ultrasound intraoperatively. We resected the tumor, including a parenchymal margin of 1 cm. around the tumor that was apparently healthy on gross examination. In some cases temporary occlusion of the renal artery was required without kidney cooling. The renal vein was exposed throughout the procedure. After resection for hemostatic purposes we used cross stitches to secure the blood vessels along the whole incision surface. The parenchyma was filled with a gelatin sponge and sutured. Homolateral lymphadenectomy was performed only in the event of suspicious findings and not on a routine basis. Retroperitoneal drainage remained in place for 3 to 5 days. Samples were fixed with formalin for subsequent histological examination, which was done by the same anatomical pathologist. Sections were dyed with hematoxylin and eosin, and analyzed. No intraoperative frozen sections of the surgi-

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cal margins were performed. UICC and American Joint Committee on Cancer classifications were used for histological typing. In all patients followup included ultrasound every 3 months for the first year and every 6 months thereafter. Abdominopelvic CT, bone scan and chest x-ray were done 6 months after surgery and once yearly thereafter. The 53 group 1 patients were followed an average of 61 months (range 14 to 133), while the 7 in group 2 were followed an average of 39 months (range 3 to 100). RESULTS

Group 1. All patients had stage pT1N0M0 disease. No patients had intraoperative evidence of multifocality. Mean pathological diameter of the primary lesion was 2.6 cm. (range 1.2 to 6). Histological evaluation revealed clear cell carcinoma in 43 cases (79%), papillary adenocarcinoma in 2 (4%), oncocytoma in 5 (12%) and mixed forms in 3 (5%). Nuclear Fuhrman grade was 1 to 3 in 51%, 42% and 7% of the cases, respectively. Peritumoral tissue that appeared healthy on gross examination showed satellite lesions instead in only 3 cases (5.6%), which were located within the 10 mm. resection. Mean distance from the primary tumor was 5.3 mm. The intraoperative and optical surgical margin (10 mm.) correlated highly with the pathological surgical margin. All satellite tumors were confined inside of pathological margins. Mean satellite lesion size was 2.3 mm. (range 1.2 to 3). Histological examination of secondary lesions revealed papillary adenocarcinoma, oncocytoma and papillary adenoma in 1 case each. In all patients the primary pathological finding was clear cell carcinoma. Multifocal disease did not correlate with primary tumor size. At a mean followup of 61 months (range 14 to 133) none of the patients had local recurrence or retroperitoneal secondary lymphadenomegaly. However, at 20 months 1 patient with primary clear cell carcinoma had an asynchronous contralateral lesion, which was also treated with nephron sparing surgery. This case was not included in our study. At 25 months after surgery 1 patient had metastases to the mediastinal lymph nodes, as confirmed histologically via biopsy. He was treated with immunotherapy but died 5 months later. In this case the primary tumor was papillary adenocarcinoma. Another patient died 30 months after surgery due to systemic disease spread. Again the primary tumor was papillary adenocarcinoma. The cancer specific survival rate in this group was 96.3% at a mean followup of more than 5 years. No patients who died had multifocal disease. Group 2. These 7 patients (total of 10 treated) had stage pT1N0M0 disease with no intraoperative evidence of ipsilateral multifocality. Mean pathological diameter of the lesions was 3.2 cm. (range 1.5 to 4). Grade was 1 and 2 in 20% and 80% of cases, respectively. Histological evaluation showed clear cell carcinoma in 8 patients (70%), papillary adenocarcinoma in 1 (20%) and oncocytoma in 1 (10%). Examination of peritumoral tissue in 1 case (10%) of bilateral renal carcinoma revealed papillary adenocarcinoma in the right kidney and oncocytoma in the left kidney. Macroscopically healthy tissue around the latter showed a satellite lesion with a diameter of approximately 3 mm. that was located about 4 mm. from the primary lesion. Histological examination of the secondary lesion revealed papillary adenocarcinoma, as in the right kidney. The cancer specific survival rate in this group was 58% at a mean followup of 39 months. There was no local recurrence. Patients died of systemic disease. The table lists all results. DISCUSSION

Conservative surgery is currently indicated for 3 categories, namely imperative, relative and elective operations.1

Patient characteristics and results No. pts. Mean age Mean tumor size (cm.) % Histological findings: Clear cell Papillary Oncocytoma Mixed forms % Grade: 1 2 3 % Peritumoral satellite lesions Mean distance from primary lesion (mm.) Mean followup (mos.) % Ca specific survival There were no local recurrences.

Group 1

Group 2

53 56.8 2.6

7 65 3.2

79 4 12 5

70 20 10 0

51 42 7 5.6 5.3 61 96.3

20 80 0 10 4 39 58

Imperative indications involve a single kidney anatomically or functionally, or synchronous bilateral lesions. Independent of the results these indications are not in question. Nevertheless, cancer specific survival results are 88.2% and 73% at 5 and 10 years, respectively. These rates improve even further when tumors smaller than 4 cm. are involved (98% and 92%, respectively).5 Relative indications for nephron sparing surgery involve contralateral kidney disease, for example nephrolithiasis, chronic pyelonephritis, vesicoureteral reflux, diabetes, hypertension and so forth, in other words, all pathological entities that could potentially alter the future function of the remaining kidney. Furthermore, elective indications involve a healthy contralateral kidney and no major systemic pathological conditions. Currently elective indications for nephron sparing surgery involve lesions less than 4 cm. that are localized and peripheral. As shown in numerous series,6 – 8 In these cases nephron sparing surgery can achieve a 90% to 100% cancer specific survival rate with a 0% to 7.3% local recurrence rate for tumors less than 4.3 cm. at a followup of up to 10 years. If we consider patients with low grade lesions smaller than 3 cm., the 10-year cancer specific survival rate is 97%.7 These high survival rates with a low number of local recurrences have currently made it possible to compare nephron sparing with radical surgery. In the prospective study of D’Armiento et al of 40 patients who underwent nephron sparing (19) or radical (21) surgery the cancer specific survival rate was similar in the 2 groups at a followup of up to 98 months.8 There was 1 death per group and no local recurrence in patients treated with nephron sparing surgery. The number of patients in our series who required imperative conservative surgery was rather low and it was influenced by numerous variables. Thus, if we consider only the 53 patients in our experience who underwent elective conservative surgery, none had evidence of multifocality preoperatively or intraoperatively. Obviously there was the possibility that other satellite tumors were present beyond the range of the peritumoral tissue resected. We always grossly inspect all kidney surfaces to assess macroscopical multifocal disease. Presumably most small unknown lesions remain silent because they are benign or perhaps followup is too short, particularly in elderly patients. In regard to macroscopically healthy peritumoral tissues satellite microlesions that did not correlate with the primary tumor were detected in only 3 cases (5.6%), including 2 that were histologically benign and only 1 with papillary adenocarcinoma micro-foci with clear cell carcinoma as the primary tumor. Total cancer specific survival in our patients was 96.3% at a mean followup of more than 5 years. None of the patients had local recurrence or locoregional lymph node metastasis. None of the 3 patients with microscopic satellite lesions had local recurrence and all are currently diseasefree. Two patients died of systemic disease.

SURGICAL MARGINS AFTER NEPHRON SPARING SURGERY FOR RENAL CELL CANCER

Even today the problem of multifocality continues to be the most widely discussed problem in relation to nephron sparing surgery. The multifocality of renal carcinoma can be synchronous ipsilateral, synchronous contralateral or asynchronous. In terms of synchronous multifocality the literature shows highly variable rates based on the type of examination (autoptic or on resected tissue) and these rates often depend on the dimensions of serial sections examined by the pathologist. However, in most cases the reported incidence is 7% to 25%.9, 10 If we consider primary lesions smaller than 3 cm., the rate of multifocal disease is no higher than 3%.11 The incidence varies with synchronous contra lateral multifocality.12 In another autoptic study the incidence increased to 11.5%. The main problem, which to our knowledge remains to be clarified, involves asynchronous contralateral lesions. These entities may be viewed as multifocal disease, the expression of metastases or new, independent disease. Currently there is no definition of the factors that can pinpoint the risk of multifocality. Various indications have been proposed and analyzed, such as histological pattern, vascular invasion of the primary tumor,13 grade, ploidy, p53 expression14 and others. Nevertheless, at this time the only parameter that appears to be strongly associated with multifocality is histological pattern, particularly papillary adenocarcinoma,15 even if the prognosis is related only to stage.16 As in our experience, multifocal lesions have highly varied biological characteristics. Small lesions are often involved and they can almost never be assessed at preoperative staging or quite frequently even during surgery. These lesions are almost always benign or only potentially malignant. The Bell classification categorizes tumors up to 3 cm. like benign adenoma. The malignant potential of small nodules has not been established and doubling time cannot be foreseen. Low potential malignancy may explain the relatively high incidence of multifocal disease of up to 25% with a low percent of local recurrence. Presumably most lesions remain silent because they are benign or perhaps because followup is too short, particularly in elderly patients. These aspects concerning multifocality would actually appear to favor conservative treatment for certain reasons. If the incidence of multifocality were so high, conservative treatment would make it possible to intervene subsequently with residual ipsilateral disease or eventual contralateral lesions.9, 10, 15 Microscopic multifocal lesions are often benign. As a result, radical nephrectomy represents over treatment, particularly for small primary lesions, as already discussed in the literature.10 What must be minimized with nephron sparing surgery is the possibility of local recurrences attributable as an initial hypothesis to nonradical local surgery or failure to remove small satellite lesions around the tumor. As reported by Novick et al,17 in this sense enucleation-resection does not guarantee complete tumor removal, while exposing the patient to a high risk of local recurrence. Therefore, it would appear that partial resection with the removal of a section of healthy peritumoral tissue is the best treatment. In regard to the size of the resected margin in our experience and in the literature18, 19 most satellite lesions are detected 5 to 10 mm. from the tumor and, thus, a total margin of about 1 cm. is more than adequate. If we consider the experience of others who noted most satellite lesions more than 10 mm. from the tumor, thus, making the margin of safety about 20 mm.,13, 20 in most cases we would perform ample resection. This scenario would forfeit the advantages of conservative surgery, entailing more complications perhaps without achieving benefits in terms of survival and local recurrence, saving evidence to the contrary. CONCLUSIONS

Our results seem to confirm that conservative surgery has a specific role in the treatment of renal cell tumors given the

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excellent survival rate without local recurrence. Moreover, conservative surgery achieves the same results from an oncological standpoint as radical nephrectomy when tumor stage and dimensions are the same. Specifically in agreement with the literature we limit this treatment to stage T1N0M0 tumors with a diameter of less than 4 cm. In cases of a peritumoral satellite lesion our followup appears to be sufficient to allow us to conclude that complete excision avoids the risk of local recurrence. In our opinion the best option continues to be elective and imperative partial resection associated with thorough anatomical, pathological study of the tissue surrounding the tumor. We continue to use resection with a surgical margin of approximately 10 mm. to verify the incidence of peritumoral multifocality, likewise examining the real prognostic significance of any satellite lesions in the surrounding tissue. We noted a 5.6% satellite lesion rate after elective conservative surgery inside of 10 mm. margins. This percent is similar to the incidence of local recurrence in the literature. Thus, we suppose that if left in situ these lesions could evolve into local recurrence. A wider margin would sometimes indicate nephrectomy. The patient often prefers to preserve the kidney and renal function even when there are costs in terms of careful surveillance for local recurrence or new tumor formation. REFERENCES

1. Uzzo, R. G. and Novick, A. C.: Nephron sparing surgery for renal tumors: indication, techniques and outcomes. J Urol, 166: 6, 2001 2. McKiernan, J., Simmons, R., Katz, J. and Russo, P.: Natural history of chronic renal insufficiency after partial and radical nephrectomy. Urology, 59: 816, 2002 3. Lau, W. K., Blute, M. L., Weaver, A. L., Torres, V. E. and Zincke, H.: Matched comparison of radical nephrectomy vs nephronsparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc, 75: 1236, 2000 4. Costantini, E., Mearini, E., Ficola, F., Petroni, P. A., Biscotto, S., Monico, S. et al: Renal cell carcinoma: histological findings in peritumoral tissue after organ-preserving surgery Eur Urol, 29: 279, 1996 5. Fergany, A., Hafez, K. S. and Novick, A.: Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year follow up. J Urol, 163: 442, 2000 6. Belldegrun, A., Tsui, K. H., deKernion, J. B. and Smith, R. B.: Efficacy of nephron sparing surgery for renal cell carcinoma: analysis based on the new 1997 tumor-node metastasis staging system. J Clin Oncol, 17: 2868, 1999 7. Herr, H. W.: Partial nephrectomy for unilateral renal carcinoma and a normal controlateral kidney: 10 year followup. J Urol, 161: 33, 1999 8. D’Armiento, M., Damiano, R., Feleppa, B., Perdona, S., Oriani, G. and De Sio, M.: Elective conservative surgery for renal carcinoma versus radical nephrectomy: a prospective study. Br J Urol, 79: 15, 1997 9. Baltaci, S., Orhan, D., Soyupek, S., Beduk, Y., Tulunay, O. and Gogus, O.: Influence of tumor stage, size, grade, vascular involvement, histological cell type and histological pattern on multifocality of renal cell carcinoma. J Urol, 164: 36, 2000 10. Nissenkorn, I. and Bernheim, J.: Multicentricity in renal cell carcinoma. J Urol, 153: 620, 1995 11. Licht, M. R., Novick, A. C. and Goordmastic, M.: Nephron sparing surgery in incidental versus suspected renal cell carcinoma. J Urol, 152: 39, 1994 12. Grimaldi, G., Reuter, V. and Russo, P.: Bilateral non-familiar renal cell carcinoma. Ann Surg Oncol, 5: 548, 1998 13. Gohji, K., Hara, I., Gotoh, A., Eto, H., Miyake, H., Sugiyama, T. et al: Multifocal renal cell carcinoma in Japanese patients with tumors with maximal diameters of 50 mm. or less. J Urol, 159: 1144, 1998 14. Haitel, A., Wiener, H. G., Blaschitz, U., Marberger, M. and Susani, M.: Biological behavior of and p53 overexpression in multifocal renal cell carcinoma of clear cell type: an immunohistochemical study correlating grading, staging, and prolifer-

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ation markers. Cancer, 85: 1593, 1999 15. Chow, G. K., Myles, J. and Novick, A. C.: The Cleveland Clinic experience with papillary (chromophil) renal cell carcinoma: clinical outcome with histopathological correlation. Can J Urol, 8: 1223, 2001 16. Kovacs, G., Akhtar, M., Beckwith, B. J., Bugert, P., Cooper, C. S., Delahunt, B. et al: The Heidelberg classification of renal cell tumours. J Pathol, 183: 131, 1997 17. Novick, A. C., Zincke, H., Neves, R. J. and Topley, H. M.: Surgical enucleation for renal cell carcinoma. J Urol, 135: 235, 1986

18. Quan-lin, L., Hong-wei, G., Qiu-ping, Z., Jun, X. and Xi-shuang, S.: Optimal margins in nephron sparing surgery for renal cell carcinoma. Eur Urol, suppl., 1: 94, 2002 19. Sutherland, S. E., Resnick, M. I., MacLennan, G. T. and Goldman, H. B.: Does the size of surgical margin in partial nephrectomy for renal cell cancer really matter? J Urol, 167: 61, 2002 20. Schlichter, A., Wunderlich, H., Junker, K., Kosmehl, H., Zermann, D. H. and Schubert, J.: Where are the limits of elective nephron-sparing surgery in renal cell carcinoma? Eur Urol, 37: 517, 2000