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- DOI 10.18231/j.jdpo.2020.017
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Renal cell carcinoma with IVC tumour thrombus: A study of clinico-pathological outcomes
Introduction
Renal cell carcinoma (RCC) represents 2–3% of all solid cancer, and it is the third most common cancer of the urinary tract, with an incidence of 6–12 cases per 100 000 people in Western countries.[1] RCC is one of the few solid organ tumors with a predilection for vascular invasion. A pproximately 10 percent of patients with RCC have tumors associated with thrombus . It is more frequent in men than in women(1.5:1), with a peak incidence between 60 and 70 yr of age.[2] Presence of vascular invasion indicates a more aggressive biological behaviour and poses a greater challenge during surgery as well as treatment . Due to recent advances in diagnostic modalities, improved surgical techniques, perioperative care, surgical removal of the kidney with the tumor thrombus, even for tumors extending into the right atrium, can be performed relatively safely.[3] However, the prognosis of patients with RCC involving the venous system, particularly the IVC(inferior vena cava), is generally poor, despite surgical resection of RCC and tumor thrombus.[8], [7], [6], [5], [4] Kim et al. reported that the 2-year recurrence-free survival rate in patients with non-metastatic RCC involving the IVC was less than 50%.[5] Others have shown that the 5-year overall survival rate was 44%.[8], [7]
Materials and Methods
Here we present seventeen patients diagnosed with RCC and venous tumour thrombus who underwent radical nephrectomy and venous tumour thrombectomy during the study period from January 2012 to January 2015.
These patients were retrospectively analysed for clinical parameters such as signs and symptoms, duration of surgery, blood loss, units of blood transfused, hospital stay, 5 year survival and complications which were graded according to Clavien dindo. ([Table 2], [Table 1] )
Laboratory correlates studied were serum calcium, serum LDH, Histopathological diagnosis, size and location of tumour, level of tumor thrombus, IVC wall invasion, perinephric fat invasion and grade of tumour. ([Table 1] )
All patients underwent routine preoperative blood tests, chest, and abdominal computed tomography (CT), gross extension of tumor thrombus into the venous system was detected by preoperative radiological examinations, including contrast-enhanced CT, magnetic resonance imaging ([Figure 1]). The level of tumor thrombus was determined according to the Mayo classification.[9]
Pathological diagnoses were determined according to the 2018 American Joint Committee on Cancer 8th edition TNM system. Histological subtype, determined according to the 1997 World Health Organization (WHO) Heidelberg classification, was split into clear cell renal cell carcinomas (ccRCC) versus non-ccRCCs . Tumor nuclear grade was determined according to the Fuhrman system. Perinephric fat and adrenal invasions were specifically recorded.
| S. No. | Age (yrs) | Sex | C/F | Sr. calcium | Sr.LDH | Level of thrombus | Size (cm) | Histology, Grade | IVC wall invasion | Perinephric fat invasion |
| 1 | 45 | m | +nt | n | < 1.5x n | l | 7x4x8 | clear cell,grade1 | absent | absent |
| 2 | 50 | m | +nt | n | < 1.5x n | l | 9x7x8 | clear cell,grade2 | absent | absent |
| 3 | 59 | f | + nt | n | < 1.5x n | l | 5x6x4 | clear cell,grade 2 | absent | absent |
| 4 | 57 | m | +nt | high | > 1.5xn | lll | 10x8x6 | clear cell,grade3 | absent | present |
| 5 | 63 | f | +nt | n | <1.5x n | lll | 10x10x8 | clear cell,grade 4 | absent | present |
| 6 | 68 | m | +nt | n | <1.5x n | l | 5x4x6 | clear cell,grade 1 | absent | absent |
| 7 | 55 | m | +nt | n | <1.5x n | ll | 6x7x6 | clear cell, grade 2 | absent | absent |
| 8 | 56 | f | + nt | n | < 1.5x n | l | 7x7x5 | clear cell, grade 2 | absent | absent |
| 9 | 67 | m | +nt | high | >1.5xn | ll | 10x5x10 | bellini duct,grade 3 | present | absent |
| 10 | 61 | m | -nt | n | <1.5x n | I | 6x3x4 | papillary,grade 1 | absent | absent |
| 11 | 62 | f | +nt | high | <1.5x n | II | 8x4x3 | clear cell,grade 2 | present | absent |
| 12 | 54 | m | +nt | n | >1.5xn | II | 11x7x8 | chromophobe,grade 3 | present | present |
| 13 | 59 | m | -nt | n | <1.5x n | I | 6x5x6 | clear cell,grade 1 | absent | absent |
| 14 | 50 | m | +nt | n | <1.5x n | II | 7x5x4 | clear cell, grade 2 | absent | absent |
| 15 | 65 | m | +nt | high | <1.5x n | I | 5x4x3 | clear cell,grade 3 | absent | absent |
| 16 | 55 | m | -nt | n | <1.5x n | I | 9x4x5 | clear cell,grade 1 | absent | absent |
| 17 | 53 | m | -nt | n | <1.5x n | I | 10x 5x3 | chromophobe,grade1 | absent | absent |
| S. No. | Duration Of Surgery (min) | Blood Loss (ml) | No. of Bloood Transfusion (units) | Wound Infection | Other complications | Clavien - Dindo Grade | Hospital stay (Days) | Follow up (FUP) |
| 1 | 210 | 1500 | 2 | No | Nil | II | 6 | On Regular FUP |
| 2 | 250 | 2000 | 2 | No | Nil | II | 7 | On Regular FUP |
| 3 | 240 | 2200 | 3 | No | Nil | II | 7 | On Regular FUP |
| 4 | 220 | 3500 | 6 | Yes | Sepsis | IV | 12 | liver & nodal mets,lost to FUP after 3 yrs |
| 5 | 240 | 3000 | 8 | Yes | Thromboembolism | IV | 10 | Lost to FUP after 2 yr |
| 6 | 240 | 1500 | 2 | No | Nil | Nil | 6 | On Regular FUP |
| 7 | 180 | 3500 | 4 | No | Nil | II | 5 | On Regular FUP |
| 8 | 145 | 1500 | 1 | No | Nil | Nil | 4 | On Regular FUP |
| 9 | 185 | 3500 | 5 | No | Post op ileus + Seroma | III | 10 | Nodes,liver & lung mets, mortality at 4 yr |
| 10 | 180 | 1800 | 0 | No | Nil | Nil | 3 | On Regular FUP |
| 11 | 210 | 3000 | 4 | Yes | Bleeding | III | 8 | On Regular FUP |
| 12 | 200 | 2900 | 3 | No | Nil | II | 4 | Bony mets,on FUP |
| 13 | 145 | 2000 | 1 | No | Nil | I | 3 | On Regular FUP |
| 14 | 220 | 4000 | 5 | Yes | Nil | II | 6 | Nodal mets , On Regular FUP |
| 15 | 160 | 1700 | 1 | No | Nil | Nil | 3 | On Regular FUP |
| 16 | 200 | 2450 | 2 | Yes | Nil | II | 5 | On Regular FUP |
| 17 | 240 | 1980 | 1 | No | Sepsis | II | 8 | On Regular FUP |
| S. No. | Variables | Blood Transfusion (units) | Wound infection (%) | Other complications(%) | Clavien Dindo Grade | Hospital stay (Days) | 5 year survival % | |
| 1 | Age | <55 | 2.6 | 1/5 (20) | 1/5(20) | II ONLY | 6.2 | 3/5(60) |
| ≥55 | 3.5 | 4/12(33.3) | 4/12(33.3) | II,III,IV(morbidity) | 6.3 | 11/12 (91) | ||
| 2 | Sex | M | 3 | 3/13 (23) | 3/13 (23) | 3/13 (23) | 6 | 10/13 (76) |
| F | 4 | 2/4( 50) | 1/4 ( 25) | 2/4 (50) | 7.2 | 4/4 (100) | ||
| 3 | Clinical Features | present | 3.5 | 4/13(31) | 4/13(31) | II,III,III,IV(morbidity) | 6.7 | 11/13 (84) |
| absent | 2.2 | 1/4(25) | 1/4(25) | II ONLY | 4.7 | 3/4 (75) | ||
| 4 | Sr. Calcium | normal | 3 | 3/13(23) | 2/13(15) | I & II ONLY | 5.69 | 11/13 (84) |
| Increased | 4 | 2/4(50) | 3/4(75) | III & IV (morbidity) | 8.25 | 3/4 (75) | ||
| 5 | Sr. LDH | <1.5 XN | 3 | 4/14(28) | 3/14(21) | II,III | 5.7 | 13/14 (93) |
| >1.5 X N | 4.6 | 1/3(33) | 2/3(66) | II,III,IV(morbidity) | 8.6 | 2/3 (66) | ||
| 6 | Level of Thrombus | 1 | 2 | 1/10(10) | 1/10(10) | I,II,NO | 5.2 | 9/10 (90) |
| 2 | 4.2 | 2/5(40) | 2/5(40) | II,III,NO | 6.6 | 4/5(80) | ||
| 3 | 7 | 2/2(100) | 2/2(100) | IV,IV(morbidity) | 11 | 1/2 (50) | ||
| 7 | Tumour size | ≤ 7cm | 2.5 | 0 | 1/7 (14) | 1/7 (14) | 4.7 | 6/7 (86) |
| > 7 cm | 3.7 | 5/10(50) | 4/10(40) | 4/10 (40) | 7.4 | 8/10 (80) | ||
| 8 | Grade | 1 & 2 | 2.6 | 3/12(25) | 2/12(16) | II,III | 5.6 | 11/12 (91) |
| 3 & 4 | 4.6 | 2/5(40) | 3/5(60) | II,III,IV(morbidity) | 7.8 | 3/5(60) | ||
| 9 | IVC Wall Invasion | present | 4 | 1/3(33) | 2/3(66) | II,III,IV(morbidity) | 7.3 | 2/3 (66) |
| absent | 3 | 4/14(28) | 3/14(21) | II,III,II | 6 | 12/14 (85) | ||
| 10 | Perinephric Fat Invasion | present | 5.6 | 2/3(66) | 2/3(66) | I,II,IV(morbidity) | 8.6 | 1/3 (33) |
| absent | 2.7 | 3/14(21) | 3/14(21) | II,III,NO | 5.7 | 13/14 (93) |
Results and Discussion
Mean age of patients in our study was 57 years and male to female ratio was 3:1. Patients with age >55 yrs and females required more blood transfusion, had more wound infections and higher grade of Clavien complications (III & IV) than patients with age <55 yrs but interestingly 5 yr survival was more (90%) in older age group and females. Similar to other studies in our study also age and gender did not significantly affect overall survival .
Symptomatic patients (flank pain, abdominal mass and hematuria) had longer duration of surgery, more blood loss, more blood transfusion, higher rate of wound infections, higher Clavien Dindo grade and more hospital stay than asymptomatic patients, but 5 yr survival was more in symptomatic group.
Hypercalcemia has been reported as the most common paraneoplastic syndrome , affecting between 13% and 20% of patients.[10] It has been reported to be associated with high-stage lesions in about 75% of cases, but found to have no significant correlation with tumor grade and survival.[11] But in our study both hypercalcemia and higher LDH level were associated with higher rate of blood transfusion, wound infection and higher Clavien grade complications and longer stay. A meta-analysis demonstrated that an elevated serum LDH level was connected to a poor prognosis for patients with RCC and as a prognostic indicator could be utilized to divide risk stratification and formulate individualized treatments for patients with RCC.[12]
Pathological examination ([Figure 2]) demonstrated that 13 out of 17 patients had clear cell carcinoma, 1 patient had bellini duct carcinoma, 2 had chromophobe,and another 1 had papillary variant.[13]
Consistent with other series[14], in our study tumor size was an important prognostic factor, patients with tumour size > 7 cm had more blood loss, more wound infection, other complications, greater clavien grade (III,IV), longer hospital stay than patients with tumour size <7 cm. Our findings support the role of tumor size as a very important predictor of outcome.
In our study there were 6 patients with Fuhrman grade 1 and 2 ,4 patients with grade 3 and one patient with grade 4 respectively. Terakawa et al concluded that in patients with RCC involving the IVC, biological aggressiveness is characterized by tumor grade rather than tumor extension and grade has more potential prognostic importance; therefore, more intensive multimodal therapy should be considered in patients with high grade RCC with tumor thrombus extending into the IVC.[15] The importance of tumor invasion in the perinephric fat and its negative impact on prognosis for patients with RCC invading the RV and IVC had been described by Leibovich in 2005 and more also by Ficarra.[17], [16], [7] Although some RCC with vein wall invasion can be cured surgically, recurrence developed in a significant proportion of patients, as reported in the review paper by Kirakali and van Poppel.[9] In three of our patients IVC wall and peri nephric fat invasion was present. Similar to other studies, our study showed that patients with higher grade (3,4), peri nephric fat invasion and ivc wall invasion had greater blood loss, more wound infection and other complications, higher clavien dindo grade, more hospital stay and lesser 5 year survival, as compared to cases in which these histopathological findings were absent.
A case to be brought to notice was that of a rare histopathological entity of collecting duct carcinoma ([Figure 3] a,b), which was associated with tumour thrombus extending all the way into the inferior vena cava (IVC) and extensive retroperitoneal lymphadenopathy. ([Figure 4])
The tumour thrombus extension was level I in ten (58 %), level II in five cases(29%), level III in two cases (11 %). In our study, the mean blood loss in levels I – III tumour thrombus were 1863 mL, 3380 mL, 32 50 ml respectively and there was more wound infection, other complications of higher clavien dindo grade ,more hospital stay and mortality in patients with level II and III thrombus than those with Level I thrombus. Similar to our study, other authors have also reported decreased survival in patients with tumor thrombus involving the IVC.[20], [19], [18], [7]
Clavien dindo complications were grade I in 1 case, grade II in 7 cases, grade III in 2 cases, grade IV in 3 cases, After surgery, the majority of patients with level III thrombus had to stay in ICU for > 24 h with a median time of 3 days One of the patient developed prolonged paralytic ileus prompting insertion of percutaneous drain for retroperitoneal collection which was removed after 2 weeks, two patients had sepsis, 1 patient had bleeding and 1 had thromboembolism, all of which were managed with medical treatment and minor interventions.[21]
During follow up period, three patients developed metastasis out of two patients with nodal and liver metstases one was lost to follow up and another died, one patient with bony metastasis was referred to oncologist for further treatment and is still on follow up, except one more patient all others are on regular followup.
Follow-up schedule
Patients were evaluated for postoperative recurrence and general condition by blood count, biochemistry analysis, chest x-ray and abdominal CT every 3 months for the first year, and every 6 months thereafter.
Conclusion
Radical nephrectomy and venous tumour thrombectomy still remains a challenging procedure testing surgical acumen & skill of the surgeon involved.
The presence of a Venous tumour thrombus, with its associated risks of venous congestion and distal embolism, adds urgency to the management of these patients. In addition, the often associated parasitic vasculature and collaterals developing as a result of vena caval occlusion increase the technical difficulty of nephrectomy and achieving a tumour free resection.
Although this is a retrospective descriptive study including a relatively small number of patients with a short follow-up period, the present findings suggest that with detailed perioperative planning and multidisciplinary efforts, the procedure could be performed with an acceptable morbidity and mortality.
Furthermore, various multivariate analysis have demon strated that multiple histopathological variables such as clinical stage, tumor type-clear cell versus nonclear cell, perinephric invasion, IVC wall invasion and more importantly tumour grade have a strong impact on the morbidity and moratlity of these patients and also stratify the subgroup in which adjuvant therapy is essential.
Source of funding
None.
Conflict of interest
None.
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