Section 2 -

Staging of Renal Cell Carcinoma Stephen M. Bonsib

Renal cell carcinoma (RCC) 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 remains the single most important prognostic feature in renal cell carcinoma (RCC). Stage is also important in patients with bilateral tumors where the outcome is determined by the individual stage of each tumor. Therefore accurate staging of a renal tumor is our most important responsibility. The first staging system for RCC was formulated by Flocks and Kadesky in 1958. The Robson staging system followed in the 1960s and remained in vogue throughout the 1970s and 80s. The most widely used staging system today is the TNM system formulated by the American Joint Commission on Cancer (AJCC) and the International Union Against Cancer (UICC). All 3 systems 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. Each classification has been shown in large series to stratify patient outcomes by stage, as shown in the tables below. Regrettably, a significant number of patients succumb to disease despite presenting with putatively renal limited disease at diagnosis. A lofty goal would be to define a renal limited category with better patient survivals. It is possible that the 2002 formulation may fulfill this objective as discussed below. Table 1: 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% Table 2: 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% TNM Formulation The TNM staging system is a dynamic formulation, undergoing periodic revisions. Although its capacity to evolve with advances in understanding tumor biology is strength, it creates difficulties in evaluating the literature when attempting to compare studies whose patients have been staged using different TNM versions. Table 3 illustrates the major T-stage differences between the 1978, 1987, and 1997 formulations. Table 3: Comparison of Three TNM Formulation T stage 1978 TNM 1987 TNM 1997 TNM pT1 "Small tumor" < 2.5 cm > 2.5 cm pT2 "Large tumor" < 7.0 cm > 7.0 cm pT3 Perinephric spread -- -- pT3a -- Perinephric/adrenal ext Perinephric/adrenal ext pT3b -- RV involved RV /VC below diaph pT3c -- VC below diaphragm VC above diaphragm pT4 Adjacent organ or abdominal wall -- Ext beyond Gerota's fas. pT4a -- Ext. beyond Gerota's fas. -- pT4b -- VC above diaphragm -- The final patient stage incorporates nephrectomy pathologic features, with other clinical and pathologic data related to lymph nodes involvement and metastases as shown below. Table 4: 2002 TNM Staging pT1 pT2 pT3 pT4 N M Stage I X Stage II X Stage III X Or pT 1-3 Any N Stage IV X N 0-1 Or any pT N 2 Or any pT N 0-2 X 2002 TNM Formulation The 2002 TNM formulation introduced several revisions of the 1997 version following important clinical and pathologic studies of the late 1990s and early 2000s. pT1 Subdivided into: pT1a - tumor 4 cm or less pT1b - tumor greater than 4 cm to 7 cm. The rationale for pT1 subdivision was based upon outcome data that indicates different recurrence rates and patient outcomes for pT1 tumors 4-5 cm, compared to larger tumors (Table 5). In a recent European multi-institutional validation study of 2217 patients with pT1a, pT1b, and pT2 tumors, excellent stratification in 5- and 10-year disease-specific survival was demonstrated for clear cell renal cell, although not for papillary renal cell carcinoma. Table 5: 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 Zisman 2001 661 RCCa 4.5 cm Igarashi 2001 333 RCCa (96%CC) 4 cm Cheville 2001 277 RCCa 5 cm Hafez 1999 485 RCCa 4 cm pT3 pT3 a, b, and c were expanded: pT3a: includes tumor invasion of renal sinus fat pT3b: includes involvement of segmental (muscle-containing) branches p3Tc: includes invasion of wall of VC (even if below the diaphragm) pT3a and b were expanded because renal carcinomas, especially clear cell renal cell carcinoma, has been shown to most often extend beyond the kidney by invading the renal sinus. The incidence of sinus invasion increases markedly for tumors in the 4-5 cm range (Graph 1). Since most sinus invasive tumors involve muscle containing veins of the renal sinus, this may explain the outcome studies (Table 4) that show patient outcomes markedly diminish for tumors larger than 4-5 cm. Graph 1. Relationship between renal sinus invasion and tumor size: 120 clear cell renal cell carcinoma (J Urol 174:1-4, 2005) Future Staging Considerations pT2 Tumors, should the definition be changed? Bonsib has shown (Graph 1) that for tumors 4-5 cm, renal sinus invasion is common, and for tumors that exceed 7 cm, sinus involvement is invariable (>97%). The pT2 category, therefore, contains few tumors (<1%) when cases are properly examined for sinus involvement minimizing the utility of the category as currently defined. pT2 should be redefined, possibly reducing it to 4 cm, and deleting subdivision of pT1. In contrast to the above recommendation, the Mayo Clinic group has argued for subdivision of pT2 into pT2a (tumors 7-10 cm) and pT2b (tumors >10 cm) based upon study of 544 patients treated between 1970 and 2000. They showed a survival difference for "renal limited" tumors 7-10 cm versus tumors >10 cm. Bonsib's data suggests, however, that a substantial fraction of clear cell carcinomas > 7cm are in fact pT3 tumors. Assessment of sinus invasion in archival material is difficult since the cases were not handled to evaluate that feature raising questions regarding the true stage of their tumors. Adrenal gland invasion, should it be incorporated into pT4? Adrenal gland involvement can occur by hematogenous metastasis or by direct extension. Metastases classified in the TNM as M1, occurs in 5%, and correlates with large tumors (ave. 9.8 cm) and high stage (>80% pT3a or higher). Adrenal gland involvement is included with perinephric fat invasion in 2002 TNM as pT3a. Recent studies have shown that with direct adrenal invasion is there is no difference in survival between pT4 tumors and pT3 tumors with direct adrenal invasion, leading to the suggestion that direct extension should be categorized as pT4 in future TNM revisions. Final Comments: There is little doubt that sinus invasion is the most common route of external extension and usually involves sinus veins. The 2002 TNM pT3 revision to include sinus involvement should shift cases that previously would have been categorized as pT1/pT2 to the pT3 category, thereby, improving the survival curves for truly renal limited Stage 1 and 2 tumors, while worsening survival curves for stage 3 disease (see Table 6). Table 6: Preliminary data: Renal Limited Tumors vs Sinus Invasive Tumors Patients with Metastases or Dead of Disease [Bonsib, S. unpublished data] < 6 months 6-12 month 1-3 years > 3 years Total Sinus pos 22/30 5/8 13/17 2/7 42/62 (68%) Sinus neg 1/17 1/11 1/21 0/10 3/60 (5%) Total cases 122 cases This will first require pathologists to incorporate a new strategy for specimen evaluation differing from that learned during training or applied for years in practice. The protocol must emphasize appropriately sampling of the tumor sinus interface. Secondly, academicians reporting outcome data relative to tumor stage should consider the staging of archival material collected prior to 2002 as suspect, and must consider only including cases accessioned after their laboratory implemented evaluation protocols that satisfy the new staging definitions in future outcome analyses. References 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. Radical nephrectomy for renal cell carcinoma. J Urol 89:37, 1963. Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol 101:297-301, 1969. Hermenek P, Sobin LH. TNM Classification of Malignant Tumours, 4th ed. Berlin: Springer-Verlag, 1987. 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. Bonsib SM, Gibson D, Mhoon M, Greene GF. Renal sinus involvement in renal cell carcinoma. 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, S. T2 Clear cell renal cell carcinoma is a rare entity: a study of 120 clear cell renal cell carcinomas. J Urol 174:1-4, 2005 Ficarra VF, Schips L, Guillè F, et al. Multiinstitutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma. Cancer 104:968-974, 2005. Siemer S, Lehmann J, Kamradt, J, et al. Adrenal metastases in 1,635 patients with renal cell carcinoma: outcome and indications for adrenalectomy. J Urol 171:2155-2159, 2004. Han K-R, Bui MHT, Pantucl, AJ, et al. TNM T3a renal cell carcinoma: adrenal gland involvement is not the same as perinephric fat involvement. J Urol 169: 899-904, 2003. Thompson RH, Cheville, JC, Lohse CM, et al. Reclassification of patients with pT3 and pT4 renal cell carcinoma improves prognostic accuracy. Cancer 104:53-60, 2005. Frank I, Blute ML, Leibovich BC, et al. pT2 classification for renal cell carcinoma. Can its accuracy be improved?