Case 2 -

Kidney and Adrenal, Left Radical Nephrectomy Stephen M. Bonsib Louisiana State University Health Sciences Center Shreveport, LA

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Case History: A.B is 54-year old female who presented to University Hospital with dyspnea and chest pain. A pulmonary work up revealed a 2 cm lung mass. A wedge excision contained a clear cell carcinoma consistent with a metastasis. A urology consult was obtained and an 11 cm left renal mass was identified leading to left radical nephrectomy. The nephrectomy specimen was opened through the renal venous system. It demonstrated a 10.5 cm multinodular, focally cystic, yellow mass with a central region of sclerosis and a separate zone of necrosis. Extension beyond the peripheral renal capsule and extension into the central sinus fat was not identified. The main renal vein was not involved. However, a 2 mm nodule of yellow tumor was noted within a large vein in the renal sinus, 1 cm from the main tumor. A second 0.6 cm yellow cortical nodule was noted several cms from the dominant mass. Microscopic evaluation revealed a clear cell renal cell carcinoma, Fuhrman nuclear grade 3. No extension into peripheral perinephric fat or central sinus fat was identified. However, the small intravenous nodule noted 1 cm from the main tumor and the separate 0.6 cortical nodule were both clear cell renal cell carcinoma. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer General Comments: Renal cell carcinoma (RCC) is has a reputation for unpredictable behavior with unusual sites of metastases, spontaneous regression of metastases, long term survival with metastases and long interval between nephrectomy and subsequent metastases. Despite biologic eccentricities the anatomic extent of disease, tumor stage, remains the single most important prognostic feature in renal cell carcinoma. Stage is also important with bilateral tumors where the prognosis is determined by the stage of each tumor. Although surgical therapy is the mainstay of treatment for renal cell carcinomas, molecular targeted therapies are beginning to show promise. Thus, identification of patients at risk for progression has assumed great importance. Since pathologic stage is clearly the most powerful prognostic indicator, pathologists must be familiar with the nuances of staging systems so that dissection protocols and histologic sampling strategies can be designed to achieve an accurate pathologic stage. For most oncology programs this means the American Joint Commission on Cancer/Union Internationale Contra le Cancer (AJCC/UICC) TNM staging system. Staging Systems: The first staging system for RCC was formulated by Flocks and Kadesky in 1958. This was followed by the Robson staging system introduced in the 1960s. The Robson system remained in vogue until the 1980s. Both successful in correlating tumor stage with outcomes, although there has been substantial variability in survival rates in reported series as note below. Five-year Survival Rate for Renal Cell Carcinoma by Robson Stage 1st Author Year # Patients Stage 1 Stage 2 Stage 3 Stage 4 Robson 1969 88 66% 51% 33% 13% McNichols 1981 499 67% 64% 42% 11% Selli 1983 115 93% 63% 80% 13% Golimbu 1986 326 88% 67% 40% 2% Mederios 1988 121 85% 48% 42% 0% Dinney 1992 314 73% 68% 51% 20% The most widely used staging system today is the TNM system. Although the TNM staging system has been in widespread use in North America since the 1980s, it was first formulated decades earlier. It is a dynamic formulation, undergoing periodic revisions. Although, its capacity to evolve in parallel with advances in understanding tumor biology is a strength, this creates difficulties in evaluating the literature and compare studies whose patients have been staged using different TNM versions. The table below illustrates the major T-stage differences between the 1978, 1987, and 1997 formulations. Comparison of Three TNM Formulation T stage 1978 TNM 1987 TNM 1997 TNM pT1 "small tumor" < 2.5 cm < 7.0 cm pT2 "large tumor" > 2.5 cm < 7.0 cm pT3 perinephric spread -- -- pT3a -- perinephric or adrenal extension perinephric or adrenal extension pT3b -- renal vein involved renal vein or VC below diaphragm pT3c -- VC below diaphragm VC above diaphragm pT4 adjacent organ or abdominal wall -- Extension beyond Gerota's fascia pT4a -- extension beyond Gerota's fascia -- pT4b -- VC above diaphragm -- All three staging systems, Flocks and Kadesky, Robson and TNM have in common a renal-limited category, a category for local spread and a category for distant spread. The TNM classification differs from its predecessors by having 2 categories for renal-limited disease, pT1 and pT2. All 3 classifications have been shown in multiple large series to correlate with patient outcome. In the table below survival data from the National Cancer Data Base is shown using the 1987 formulation. Collated Survival Data - AJCC/UICC 1987 version Stage Diagnosis Year 1 Year 2 Year 3 Year 4 Year 5 I 100% 94.5% 91.4% 89.5% 87.2% 84.7% II 100% 94.3% 87.4% 87.4% 85.0% 82.9% III 100% 83.1% 73.4% 68.0% 63.1% 59.8% IV 100% 36.6% 22.6% 16.7% 13% 11.1% Unfortunately, with all staging systems at least 15-20% of patients presenting with "putatively" renal-limited disease at diagnosis (pT1 and pT2 in the TNM system), succumb to metastatic disease. In the 1980s the National Wilms Tumor Study, following the seminal observations of Bruce Beckwith, identified the importance of the renal sinus, particularly renal sinus veins, in tumor dissemination. In an effort to determine if similar biologic behavior occurs with renal cell carcinomas of adults, the author initiated a prospective analysis of renal cortical neoplasms in 1998. To date over 300 renal cortical neoplasms have been examined by the author focusing on renal sinus involvement. The major findings of these studies can be briefly summarized as follows: Renal sinus involvement is the primary (initial site and most common site) of tumor extension outside of the kidney for all RCCs. Observations applicable to clear cell renal cell carcinoma, but not necessarily to other types of renal cell carcinoma. Sinus venous involvement represents the initial site of extrarenal extension for clear cell RCC; it first gains access to large tumor draining vein(s) while still renal-limited and then extends along these venous channels into the renal sinus. Clear cell RCC extends into the sinus fat most often from sites of initial intravenous involvement by invading through the vein wall into sinus fat. When large sinus veins +/- the main renal vein are occluded by tumor, retrograde venous spread occurs into the non neoplastic cortex. When a clear cell RCC is 4-5 cm size range or larger, renal sinus involvement is extremely common. In keeping with #5 above, pT2 clear cell RCC is rare (1-5% of cases) if careful examination of the renal sinus is performed as shown in the graph below. Relationship between renal sinus invasion and tumor size: 120 clear cell renal cell carcinoma In 2002 the TNM formulation was last modified. Two major revisions of the 1997 version were introduced. pT1 was subdivided into two categories: pT1a - tumor 4 cm or less pT1b - tumor greater than 4 cm to 7 cm. pT3 criteria was expanded to include renal sinus involvement: pT3a - tumor invades renal sinus fat pT3b - tumor invades segmental (muscle-containing) branches (of renal sinus veins) Justification for pT1 subdivision was based upon outcome data. A number of studies (but not all) published before the 2002 TNM formulation, and subsequent, found that the recurrence rate and patient outcome appears to have a breakpoint for tumors above versus below a 4-5 cm cutoff (see Table). The 4-5 cm size range is also the point at which renal sinus involvement becomes very common, pathologic variables that I believe are related. Breakpoint in Patient Outcome versus Tumor Size 1st Author Year # Cases Tumor Type Breakpoint Ficarrio 2004 813 RCCa 5.5 cm Elmore 2003 351 RCCa 5.0 cm Frank 2002 1801 RCCa 5.0 cm Lau 2002 682 Clear Cell 4.5 - 5.0 cm Delehunt 2001 130 Clear Cell Continuous variable Zisman 2001 661 RCCa 4.5 cm Igarashi 2001 333 RCCa (96%CC) 4 cm Cheville 2001 277 RCCa 5 cm Moch 2000 487 Clear cell No cutoff in 4 - 8 cm Hafez 1999 485 RCCa 4 cm Frank et. al. in 2005 validated the pT1a and pT1b separation as shown in the figure below. [J Urol 173;1889-1992, 2005] When cases carefully examined for renal sinus involvement are staged by both the 1997 and 2002 formulation, many cases staged pT1 and pT2 by 1997 TNM, shift into pT3 by 2002 TNM criteria. If renal sinus involvement conveys prognostic importance, then one could postulate that many cases stage pT1 and pT2 by 1997 TNM that metastasized (the 15-20% alluded to above) did so because they were under staged extrarenal pT3 tumors by 2002 TNM. This postulate was tested by the Mayo Clinic group who had access the original specimens from patients with pT1 and pT2 tumors staged by 1997 TNM formulation. They found that over 50% of tumor specimens when re-examined were found to have sinus extension, and were extrarenal pT3 tumors by 2002 criteria. Final Comments: The most critical staging issue for RCC is identification of renal-limited disease versus extension beyond the kidney. The latter may entail involvement of veins of the complex renal venous system or extension into either of the two perinephric fat compartments, peripheral and renal sinus. Pathologists must employ a specimen evaluation strategy to include renal sinus evaluation which likely differs from that learned during training and applied for years in practice. Although, there are a number of nephrectomy dissection protocols in reference texts and journal articles, most were published prior to the 2002 TNM iteration and are obsolete since they do not address renal sinus examination. Three articles published after 2002 contain useful recommendations for specimen dissection that include the renal sinus are referenced in the bibliography. The author's preferred dissection approach is to open through the collecting system and mid point of the tumor, followed by careful perinephric fat removal. A series of parallel slices through the specimen is then performed. This allows excellent display of the tumor-renal sinus interface. Opening through the venous system also has merit as shown by the case presented, in which sinus vein involvement could well have been missed with other dissection strategies. This small quantity of tumor adherent to and invading the wall of a large sinus vein is all that is required to merit pT3b designation. Finally, since renal sinus invasion is almost invariable for clear cell tumors larger than 7 cm, we should be wary of diagnosing pT2 clear cell RCC without thorough sinus evaluation. Precautionary Note: Academicians reporting outcome data relative to tumor stage must recognize the limitations of archival material collected prior to 2002 that was not likely evaluated for renal sinus involvement. Thus, some cases must be under staged by 2002 TNM criteria which reduces the validity of retrospective analysis of old cases. In future outcome analyses, urologic pathologists should consider including only cases accessioned after their laboratory implemented a sampling protocol that addresses the 2002 staging parameters. If this is done, future outcome studies may reveal significantly improved survival curves for truly renal-limited pT1 and pT2 tumors, from the historic 15-20% death rate, using 1997 or older TNM staging. Final Diagnosis: Kidney and adrenal, left radical nephrectomy: Clear cell renal cell carcinomas, two separate tumors, 10.5 cm and 0.6 cm. Fuhrman nuclear grade 3. Renal sinus vein invasion identified. Final Stage: pT3b, Nx, M1 Speculation: The discontinuous focus of carcinoma with the sinus vein may be the residua of an intravenous tumor extension, most of which metastasized to the lung leading to the initial cancer diagnosis. Selected References Staging and prognostic factors: Flocks RH, Kadesky MC. Malignant neoplasms of the kidney: an analysis of 353 patients followed for 5 years or more. J Urol 79:196, 1958. Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol 101:297-301, 1969. Sobin LH, Wittekind Ch. TNM Classification of Malignant Tumours, 5th ed. New York, NY: Wiley-Liss, 1997 Green FL, Page D, Marrow M, Fritz AG, Balch CM, Haller DG, Marrow M. AJCC Cancer Staging Manual, 6th ed. New York, NY: Springer, 2002. Eble J N, Sauter G, Epstein J I, et al. World Health Organization Classification of Tumours: Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press, 2004. Shuch B, La Rochelle JC, Pantuck AJ, Belldegrun AS. The staging of renal cell carcinoma. Curr Opin Urol 18:455-461, 2008. Frank I, Blute ML, Leibovich BC, et. al. Independent validation of the 2002 AJC on cancer primary tumor classification for renal cell carcinoma using a large single institution cohort. J Urol 173;1889-1992, 2005. Ficarra VF, Schips L, Guillè F, et al. Multi-institutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma. Cancer 104:968-974, 2005. Cheville J C, Lohse C M, Zincke H, Weaver A L, Blute M L. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 2003; 27:612-624. Moch H, Gasser T, Amin M B, Torhorst J, Sauter G, Mihatsch M J. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer 2000; 89:604-614. Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma. Cancer 2003, 97:1663-1671. Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration Cancer 113:78-83, 2008. Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapies. J Urol 173:1853-1862, 2005. Ficarra V, Novara G, Galfano A, Artibani W. Neoplasm staging and organ'confined renal cell carcinoma: a systematic review. Eur Urol 46: 559-564, 2004. Bonsib SM. Risk and Prognostic Factors: The Pathologist's Perspective. Urologic Clinics of North America 1999; 26:3,643-660. Editor David G. Bostwick, W. B. Saunders. Delahunt B. Histopathologic prognostic indicators for renal cell carcinoma. Semin Diag Pathol 1998; 15:68-76. Renal sinus: Guinan P, Sobin LH, Algaba F, et al. TNM staging of renal cell carcinoma: Workgroup No. 3. Union International Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80:992-93, 1997. Weeks DA, Beckwith JB, Luckey DW. Relapse-associated variables in stage 1 favorable histology Wilms' tumor. A report form the National Wilms' Tumor Study. Cancer 60:1204-1212, 1987. Bonsib SM, Gibson D, Mhoon M, Greene GF. Renal sinus involvement in renal cell carcinomas. Am J Surg Pathol, 24: 451, 2000. Bonsib SM. The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell carcinomas. Am J Surg Pathol, 28: 1594, 2004. Bonsib SM. T2 clear cell renal cell carcinoma is a rare tumor: a study of 120 clear cell renal cell carcinomas. J Urol 174:1-4, 2005. Bonsib, SM. Renal veins and venous extension in clear cell renal cell carcinoma. Mod Pathol 20: 44-45, 2007. Grignon D, Paner GP. Renal cell carcinoma and the renal sinus. Adv Anat Pathol 14:63-68, 2007. Thompson RH, Leibovich BC, Cheville JC, Webster WS, Lohse CM, Kwon ED, Frank I, Kinnkcke H, Blute ML. Is renal sinus fat invasion the same as perinephric fat invasion for pT3a renal cell carcinoma? J Urol 174:1218-1221, 2005. Thompson RH, Blute ML, Krambeck ML, Lohse CM, Magera JS, Leibovich BC, et. al. Patients with pT1 renal cell carcinoma who die form disease after nephrectomy may have unrecognized renal sinus fat invasion. Am J Surg Pathol 31: 1089, 2007. Renal neoplasm dissection protocols Che M, Grignon DJ. Handling and reporting of tumor-containing kidney specimens. Clin Lab Med 25:417-432, 2005. Fleming S, Griffiths DFR. Best Practice No 180. Nephrectomy for renal tumour; dissection guide and dataset. J Clin Pathol 58:7-14, 200 Bonsib SM. Macroscopic assessment, dissection protocols, and histologic sampling strategy for renal cell carcinomas. Diag Histopathol 14: 151-156, 2008.