Renal cell carcinoma clinically involving adjacent organs

Experience with aggressive surgical management

Authors


Abstract

BACKGROUND.

Historically, patients with nonmetastatic renal cell carcinoma (RCC) involving adjacent organs have been considered inoperable and incurable. The oncologic efficacy of an aggressive surgical approach was evaluated in a selected subpopulation of RCC patients. Further, an attempt was made to define the clinical and pathologic characteristics predictive of surgical failure.

METHODS.

With Institutional Review Board approval, the institutional nephrectomy database of 3470 patients treated at MD Anderson Cancer Center from 1990 to 2006 was searched for RCC patients treated with radical nephrectomy and resection of at least 1 adjacent organ thought to be directly involved by RCC. Patients with nonmetastatic RCC and a minimum follow-up of 6 months were included in the analysis.

RESULTS.

In all, 30 patients with clinical T4NxM0 RCC and median follow-up of 32.3 months (range, 8.5–140.1) met the study inclusion criteria and comprise the dataset for the analysis. On pathologic evaluation 60% of patients were clinically overstaged, as only 12 (40%) of 30 patients demonstrated direct invasion into adjacent organs resected. None of the clinical tumor characteristics predicted a finding of pathologic T4 RCC. Nodal involvement and pathologic T stage were significant independent predictors of disease recurrence (hazard ratio [HR] 3.726, P = .043, and HR 2.414, P = .045, respectively) and cancer-specific survival (HR 17.145, P = .002, and HR 3.791, P = .024, respectively). Disease recurred in 11 of 18 (61.1%) of <pT4 patients and in 10 of 12 (83.3%) of pT4 patients at a median 13.3 and 2.3 months, respectively; 13 (73.3%) <pT4 patients and 5 (41.7%) pT4 patients were alive at the time of analysis.

CONCLUSIONS.

True pathologic involvement of adjacent organs by RCC cannot be predicted from pre- or intraoperative parameters. A significant proportion of patients clinically suspected of having T4 RCC are downstaged, and benefit from aggressive surgical resection with en bloc removal of involved organs. Cancer 2007. © 2007 American Cancer Society.

The incidence of renal cell carcinoma (RCC) has risen at a rate of approximately 3% per year since the 1970s and in 2006 an estimated 12,840 patients will die of RCC.1 In addition to increased radiologic detection of ‘incidental’ renal tumors, the incidence of advanced tumors and death from disease in patients with RCC has also increased.2

Tumor invasion beyond Gerota fascia into adjacent organs, without concomitant metastatic disease, is relatively unusual. Large retrospective series report a 5% to 15% incidence of pT4 RCC, the majority of which were associated with synchronous metastases.3, 4 The published literature addressing the group of patients with nonmetastatic RCC with adjacent organ involvement is scant and contradictory, but most reports suggest that less than 5% of patients survive 5 years after surgery.5–9 Consequently, despite no clinical evidence of metastatic disease, patients with suspected T4 RCC are often labeled ‘unresectable’ and ‘incurable’ and are offered palliative treatment measures.

It is well established that surgical removal of the primary tumor remains the mainstay of treatment for localized and locally advanced RCC, and a fundamental part of an integrated multimodality treatment plan for patients with metastatic RCC.6, 10–12 Furthermore, clinical staging of renal lesions is inaccurate, and downstaging is frequently observed on final pathologic review.13 As a result, at our institution all patients with suspected T4 RCC, no clinical evidence of metastases, and the ability to tolerate a surgical intervention are offered surgical removal of all affected organs with curative intent. We report surgical and disease-specific outcomes of a unique subset of patients in whom involvement of adjacent organs by RCC was suspected intraoperatively and removal of all gross malignant disease was achieved after radical nephrectomy with en bloc resection of adjacent involved viscera.

MATERIALS AND METHODS

All studies were undertaken with the approval and institutional oversight of the Institutional Review Board (IRB) for the Protection of Human Subjects at the University of Texas M. D. Anderson Cancer Center. From 1990 to 2006 the institutional nephrectomy database of 3470 entries was searched for patients who underwent radical nephrectomy with resection of at least 1 adjacent organ thought to be directly involved by a renal mass. Patients with less than 6 months follow-up, incomplete resection, non-RCC pathology, and metastatic disease at the time of nephrectomy were excluded from analysis. Comprehensive clinical and pathologic data elements were collected and entered into an IRB-approved database. Multiple data reviews and quality checks were performed to assure the accuracy and completeness of all data elements.

RCC staging was assigned according to the AJCC 2002 TNM classification.14 Tumor grade was determined using the Furman grading system. Tumor histology was classified according to 2004 WHO criteria.15 All pathological findings were reviewed by 2 experienced genitourinary pathologists specializing in RCC.

All malignant tissue was surgically removed with open radical nephrectomy, regional lymphadenectomy, en bloc resection of all involved adjacent organs, and removal of venous tumor thrombus if present.

Follow-up consisted of a physical examination, serum chemistry evaluation, liver function tests, chest radiography, and abdominal computed tomography, performed every 3 months for the first 2 years and semiannually thereafter. Adjuvant therapy was not routinely offered in the setting of nonmetastatic RCC; however, 4 (33%) pT4 patients and 5 (28%) <pT4 patients participated in adjuvant therapy protocols. Upon disease progression 8 (80%) of pT4 patients and 9 (82%) of <pT4 patients received systemic immunotherapy and/or chemotherapy. Adjuvant and salvage systemic therapies consisted of a variety of immunotherapies including heat shock protein vaccine, interleukin-2, and interferon. Some patients were treated with systemic chemotherapeutic agents such as thalidomide, 5-flurouracil, and gemcitabine. When patients died the cause of death was determined by the treating physicians, by chart review corroborated by death certificates, or by death certificates alone.

The Fisher exact test and the chi-square test were used to evaluate the association between clinical and pathologic variables. Differences in variables with a continuous distribution across dichotomous or ranked categories were assessed using the Mann-Whitney U-test or the Kruskal-Wallis nonparametric analysis of variance, respectively. The Kaplan-Meier method was used to calculate survival functions and differences were assessed with the log-rank statistic. Univariate and multivariate survival analyses were performed using the Cox proportional hazard regression model. Statistical significance in this study was set as P ≤ .05. All reported P-values are 2-sided. All analyses were performed with SPSS (Chicago, Ill, v. 13.0).

RESULTS

A total of 30 patients met protocol inclusion criteria, that is, pathological and/or clinical T4NxM0 RCC fully resected with radical nephrectomy, en bloc removal of adjacent involved organ(s), and regional lymphadenectomy. The number of organs removed en bloc with nephrectomy specimen was 1 in 22 (73.4%) patients, 2 in 4 (13.3%) patients, 3 in 3 (10.0%) patients, and 4 in 1 (3.3%) patient. On final pathologic specimen evaluation, 18 (60%) patients were downstaged to <pT4 disease (2, pT2; 16, pT3). All surgical margins were negative. Colon, pancreas, and diaphragm were the most commonly infiltrated adjacent organs (in 5, 3, and 3 patients, respectively). Pathologic invasion into spleen, liver, and bowel mesentery was seen in 2 patients each. Clinical and pathologic features of study patients and association with pT stage are shown in Table 1. Patients with pT4 RCC were more likely to harbor direct tumor invasion into the ipsilateral adrenal gland. None of the other characteristics differed significantly between <pT4 and pT4 RCC patients.

Table 1. Clinical and Pathologic Patient Characteristics
 All<pT4pT4P
  1. SD indicates standard deviation; ECOG, Eastern Cooperative Oncology Group.

No. patients (%)3018 (60.0)12 (40.0) 
Mean age, y ±SD58.0±10.657.9±11.458.0±9.5.989
Gender (%)
 Women7 (23.3)2 (28.6)5 (71.4) 
 Men23 (76.7)16 (69.6)7 (30.4).084
Side (%)
 L15 (50.0)7 (46.7)8 (53.3) 
 R15 (50.0)11 (73.3)4 (26.7).264
ECOG performance status (%)
 018 (60.0)12 (66.7)6 (33.3) 
 112 (40.0)6 (50.0)6 (50.0).373
Presenting symptoms (%)
 None4 (13.3)2 (50)2 (50) 
 Local14 (46.7)9 (64.3)5 (35.7) 
 Systemic12 (40.0)7 (58.3)5 (41.7).563
Radiologic adjacent organ invasion (%)
 Absent10 (33.3)8 (80.0)2 (20.0) 
 Present20 (66.7)10 (50.0)10 (50.0).235
Fuhrman grade (%)
 Grade 2 or 317 (56.7)12 (70.6)5 (19.4) 
 Grade 413 (43.3)6 (46.2)7 (53.8).450
Mean tumor size (cm) ± SD13.3±5.012.9±5.413.8±4.6.676
Direct adrenal extension (%)
 Absent24 (80.0)17 (70.8)7 (29.2) 
 Present6 (20.0)1 (16.7)5 (83.3).026
Venous involvement (%)
 Absent19 (63.3)10 (52.6)9 (47.4) 
 Present11 (36.7)8 (72.7)3 (27.3).442
Lymph node status (%)
 N020 (66.7)13 (65.0)7 (35.0) 
 N1, N210 (33.3)5 (50.0)5 (50.0).461
Lymphovascular invasion (%)
 Absent22 (73.3)13 (59.1)9 (40.9) 
 Present8 (26.7)5 (62.5)3 (37.5)1.000
Histology (%)
 Conventional23 (76.7)13 (56.5)10 (43.5) 
 Nonconventional7 (23.3)5 (71.4)2 (28.6).669
Sarcomatoid component (%)
 Absent23 (76.7)16 (69.6)7 (30.4) 
 Present7 (23.3)2 (28.6)5 (71.4).084
Mean no. organs removed ± SD1.43±0.81.2±0.41.8±1.1.068
Mean no. organs involved ± SD1.3±0.601.3±0.6<.001
No. adjuvant systemic therapy (%)
 No21 (70.0)13 (43.3)8 (56.7) 
 Yes9 (30.0)5 (55.6)4 (44.4).320

Mean estimated blood loss (EBL) (2.3 L, range, 0.3–8 L), number of red blood cell (RBC) units transfused (4.3, range, 0–18), length of hospital stay (9 days, range, 4–22 days), and perioperative complication rates were similar between <pT4 and pT4 patients (P = .330, P = .307, P = .133, P = .408, respectively). Major and minor perioperative complications occurred in 5 patients each. There were no perioperative (within 30 days of surgery) deaths.

Disease recurred in 11 of 18 (61.1%) <pT4 patients and in 10 of 12 (83.3%) pT4 patients at a median 13.3 and 2.3 months, respectively; 13 of 18 (73.3%) of <pT4 and 5 of 12 (41.7%) of pT4 RCC patients were alive at the time of analysis. Median follow-up for <pT4 RCC patients was 33.5 months (mean, 40.5 months; range, 6.1–140.0 months), whereas for pT4 RCC it was 31.0 months (mean, 33.3 months; range, 8.9–79.5 months).

On univariate (Table 2) and multivariate (Table 3) Cox proportional hazards regression analyses, pathologic T stage and presence of lymph note involvement were the only independent predictors of disease recurrence and kidney cancer-specific mortality.

Table 2. Univariate Cox Regression Analysis of Clinical and Pathologic Features for the Prediction of Disease Recurrence and Disease-Specific Mortality in 30 RCC Patients Treated With Nephrectomy and Adjacent Organ Resection
 RecurrenceKidney cancer-specific mortality
Risk ratio95% CIPRisk ratio95% CIP
  1. RCC indicates renal cell carcinoma; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group.

Age0.9590.912–1.008.1000.9560.895–1.022.188
Gender1.5020.544–4.145.4323.1560.987–10.088.053
ECOG1.1200.472–2.655.7982.4980.797–7.835.116
Symptoms at presentation0.8910.672–1.650.8910.9810.542–1.765.450
Fuhrman grade1.9800.876–4.478.1014.7091.388–15.975.013
Pathologic tumor stage (pT4 vs <pT4)4.1161.628–10.407.0033.2381.022–10.264.046
Tumor size0.6880.277–1.707.4201.1340.296–4.347.854
Adrenal involvement3.2871.153–9.372.0261.8370.483–6.991.372
Venous involvement0.9870.407–2.392.9760.5410.146–2.008.359
LVI1.7150.677–4.346.2561.4920.444–5.017.518
Lymph node metastases4.9481.634–14.980.00515.1443.723–61.594<.001
Histology (conventional vs nonconventional)1.2170.432–3.427.7102.9970.841–10.686.091
Sarcomatoid features3.1941.101–9.268.0338.3902.062–34.136.003
No. organs resected1.5160.842–2.730.1661.3040.690–2.464.414
Adjuvant systemic therapy1.5911.049–2.533.4501.1450.804–3.453.441
Table 3. Multivariate Cox Regression Analysis of Clinical and Pathologic Features for the Prediction of Disease Recurrence and Disease-Specific Mortality in 30 RCC Patients Treated With Nephrectomy and Adjacent Organ Resection
 RecurrenceKidney cancer-specific mortality
Risk ratio95% CIPRisk ratio95% CIP
  1. RCC indicates renal cell carcinoma; CI, confidence interval.

Fuhrman grade1.9800.876–4.478.1012.1780.555–8.548.265
Adrenal involvement1.9470.648–5.848.2351.8370.483–6.991.372
Lymph node metastases3.7261.043–13.314.04317.1452.742–107.214.002
Sacromatoid features0.7150.193–2.647.6153.2150.519–19.897.209
<pT4 vs pT42.4141.018–5.726.0453.7911.194–12.032.024

Figure 1 demonstrates decreased 3-year recurrence-free survival in lymph-node (LN)-positive (29% vs 10%, P = .001) and pT4 patients (28% vs 10%, P = .001). Kaplan-Meier analyses also revealed significantly decreased 3-year cancer-specific survival if metastatic LNs were discovered (66% vs 12%, P < .001) and if true pathologic invasion of visceral organs was demonstrated (66% vs 22%, P = .035) (Fig. 2).

Figure 1.

Probability of recurrence-free survival after nephrectomy stratified according to the presence of lymph node metastases and pathologic stage.

Figure 2.

Probability of cancer-specific survival after nephrectomy stratified according to the presence of lymph node metastases and pathologic stage.

DISCUSSION

Our findings indicate that involvement of adjacent organs by RCC without clinically evident systemic metastases is rare (1% of nephrectomy cohort). As seen in Table 1, patients frequently present with large, poorly differentiated renal masses, have a high likelihood of LN metastases, venous tumor thrombus, and adrenal involvement. The majority (87%) of patients present with local and/or systemic symptoms; however, all had an ECOG performance status of 0 or 1.

The tendency for RCC to initially grow locally and to parasitize vessels may account for rare patients with large primary tumors invading adjacent viscera.16 Theoretically, because of the central retroperitoneal location and the natural protective barrier of Gerota fascia, it is considerably more frequent for a renal mass to indent adjacent organs rather than to directly infiltrate them.17 Furthermore, large renal masses frequently induce a significant amount of reactive desmoplasia, obliterating surgical tissue planes, and mimicking pT4 disease.18 Our study confirmed that a majority (60%) of patients, thought to have invasion of adjacent organs clinically, were downstaged during final pathologic evaluation. Even though invasion of liver, spleen, and bowel mesentery were identified, colon, pancreas, and diaphragm were the most frequently involved structures. We were not able to identify useful patient or tumor characteristics that would predict pathologic infiltration of adjacent viscera by RCC. Whereas direct adrenal invasion was more common in pT4 lesions, none of the other clinical patient and tumor features studied correctly differentiated between true pathologic involvement of adjacent viscera and benign desmoplastic adhesions. Of note, suspicion of adjacent organ invasion on preoperative abdominal cross-sectional imaging was present in 56% of <pT4 patients and in 83% of pT4 patients, and did not accurately predict final pathologic stage (P = .235).

We have found that pathologic tumor stage and nodal status remained significant independent predictors of disease recurrence and survival after adjusting for tumor size, grade, histology, number of organs resected, direct adrenal involvement, presence of venous tumor thrombus, RCC-related symptoms at presentation, and patient performance status. In our series, 13 patients with pT2 and pT3, node-negative disease, demonstrated expected stage-appropriate disease-specific survival of 100% and 48%, respectively.3, 19 Even though patients with pT4 RCC experienced recurrence early and frequently, 2 patients (17%) remain without any evidence of disease and, overall, 5 pT4 patients (42%) are alive at a median follow-up of 38 months. Systemic adjuvant therapy was administered to 30% of patients and did not impact the recurrence rate or risk of death from RCC. Comparison of current series to open nephrectomy series, reported in the literature, revealed that concomitant resection of adjacent organs at the time of nephrectomy was associated with an increased blood loss and hospital stay; however, all patients recovered from the procedure with similar morbidity.19, 20

This series is unique in several respects. First, to our knowledge this is the first report evaluating surgical and oncologic outcomes in a rare group of patients with nonmetastatic RCC clinically involving adjacent viscera. Second, a decision about possible visceral organ involvement was made intraoperatively by the operating surgeon, without relying on preoperative radiologic imaging. The retrospective nature and relatively small number of patients are notable limitations of this study; however, 30 patients were reviewed, representing over 15 years of accrual at a tertiary referral center. Finally, surgical management of RCC involving adjacent organs is challenging, and patients in whom locally advanced RCC is suspected should be referred to centers with significant experience in managing these complex patients.

CONCLUSION

True pathologic involvement of adjacent organs by RCC is rare and cannot be predicted from preoperative or intraoperative findings, and the majority of patients in whom involvement of adjacent organs is suspected clinically are overstaged. Regardless of pathologic stage, acceptable morbidity and durable disease-free survival is expected in a significant proportion of patients after radical nephrectomy with en bloc removal of involved visceral organs.

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