TNM staging system
The TNM staging classification incorporates tumour size, node involvement and metastatic spread, as with other cancers, but also considers the prognostic impact of tumour thrombus and the extent of spread into the inferior vena cava (IVC). Using this tool the 5-year survival rate is reported to be 91%, 74%, 67% and 32% for stages I to IV . However, there has been much debate about the prognostic accuracy of this system, in particular for the precise thresholds of tumour size and the significance of tumour thrombus, perirenal/sinus fat involvement, adrenal involvement and lymphadenopathy.
Several studies examined the T1 tumour size threshold; the revision of the TNM staging system in 2002 added a subdivision of T1 tumours into T1a and T1b, using a 4-cm threshold . This has particular significance with the increasing prevalence of nephron-sparing surgery (NSS), where studies show the clinical effectiveness and safety of NSS in tumours of <4 cm .
More recently Leibovich et al. retrospectively reviewed 91 patients treated with NSS and 841 treated with radical nephrectomy for 4–7 cm RCC. When adjusted for features known to be associated with RCC prognosis, e.g. perinephric fat, renal vein and regional lymph node involvement, nuclear grade, histological tumour necrosis and histological subtype, they found no statistical differences in outcome between patients treated with NSS or radical nephrectomy for 4–7 cm RCC. Emerging data suggest that the width of tumour margin bears no relationship to the risk of disease progression, as long as complete resection is achieved [11,12].
Adrenal involvement and tumour thrombus
Tsui et al. reported the 5-year cancer-specific survival rate of stage T3 disease to be 42%, vs 83% and 57% for stages T1 and T2, respectively. However, recently several studies were reported that examined the prognostic impact of fat and adrenal invasion, and the significance of tumour thrombus level. These studies have called into question the prognostic accuracy of Stage T3 according to the 2002 TNM staging system.
Stage T3a is currently defined as tumour invasion into the adjacent adrenal gland and/or infiltration of the perinephric fatty tissue but not extending beyond Gerota’s fascia. Han et al. investigated the clinical behaviour of pT3a tumours in patients after nephrectomy. They reported that there was significantly worse survival in 27 patients with adrenal involvement than in 187 similarly staged tumours with no adrenal involvement. There were no survivors at 5 years in patients with direct adrenal involvement, compared with 36% in patients with perinephric/renal sinus fat involvement. They also noted that the survival of patients with adrenal gland involvement was similar to those tumours with involvement of adjacent organs, currently staged as T4. These findings prompted the suggestion that direct adrenal gland invasion be staged as T4.
RCC invades the venous system in 4–10% of newly diagnosed cases [14,15]. The 2002 TNM classification stratifies disease with tumour thrombus into two groups, T3b being that with tumour thrombus below the diaphragm and T3c above. Moinzadeh and Libertino , in 2004, retrospectively reviewed 153 cases of RCC with vascular venous extension, to test the assertion that level of tumour thrombus affects survival. They found that patients with tumour thrombus in the IVC below the level of the diaphragm had significantly lower survival than those patients with tumour thrombus in the renal vein. However, extent of tumour thrombus in the IVC had no statistically significant effect on cancer-specific survival rates.
Kim et al. compared 216 patients who had had nephrectomy and tumour thrombectomy with 653 patients who had nephrectomy with no thrombectomy. The 3-year recurrence-free rates for RCC were 78% for patients with no thrombus, 60% if there was renal vein involvement (T3b), 46% if there was IVC involvement below the diaphragm (T3b) and 34% if there was IVC involvement above the diaphragm (T3c). They found no significant survival difference between T3a and T3b tumours but worse survival rates for patients with T3c tumours (P = 0.009). Although the presence of venous thrombus was associated with a higher risk of recurrence and lower cancer survival rates, there was no significant difference when the data were corrected for clinical and pathological features known to be predictors of prognosis. The group therefore concluded that tumour grade, tumour stage and Eastern Cooperative Oncology Group (ECOG) performance status were better predictors of outcome than level of tumour thrombus involvement.
More recently, Leibovich et al. reviewed 697 patients including pT3a, pT3b, pT3c and pT4 tumours. In agreement with Moinzadeh and Libertino , but in contrast to Kim et al., they found that among patients with pT3b tumours, those with tumour thrombus restricted to the renal vein had significantly better survival than those with tumour thrombus extension into the IVC. Similarly they noted that patients with perinephric/renal sinus fat invasion had half the cancer-specific survival rate than patients with no fat invasion. They therefore proposed a further subclassification of T3 tumours based on tumour thrombus and fat invasion, and showed a significant improvement in prognostic accuracy for their patients.
In an interesting recent study of 227 patients with pT3–pT4 RCC , a univariate analysis of pathological stage according to the 2002 TNM staging criteria failed to show any statistically significant difference in survival. These authors reclassified tumour stage into three categories combining perirenal fat invasion, tumour thrombus level, adrenal gland and involvement of Gerota’s fascia as factors, and on multivariate analysis showed their new classification to be an independent predictive variable. The studies by Leibovich et al. and Ficarra et al. show that improvements can be made to current T3–T4 staging but further work is needed to optimize staging.
Pantuck et al. reviewed lymphadenopathy in 900 patients and its impact on survival and response to immunotherapy. Their findings supported the assertion that lymph node-positive status (N+) is associated with larger, higher grade and more locally advanced tumours. In addition they noted that not only is N+ disease more likely to be associated with metastases, but also that patients with N+ disease and metastases had significantly worse prognosis than patients with metastatic disease alone. When reviewing the response rate to immunotherapy, patients with N+ disease had poorer response rates. Interestingly, 112 patients with N+ disease who had had lymph node dissection had a statistically significant survival advantage over 17 who had not had lymph node dissection. However, they did not identify any survival advantage with lymph node dissection in those patients who clinically had negative lymph nodes.