7. VHL Disease
• Rare, autosomal dominant, familial cancer syndrome
• VHL tumor suppressor gene at chromosome 3
• One VHL allele is inherited with a mutation inactivation of the other allele
loss of VHL protein and VBC complex decrease destruction of HIF-
alfa (transcription factor) accumulate over expression of many genes
related to angiogenesis VEGF & PDGF
• Renal-cell carcinoma, arise from the inactivation or silencing of the
remaining normal (wild-type) VHL allele
• Manifestation (benign & malignant tumor or cyst):
1. CNS hemangioblastomas
2. Retinal angiomas / hemangioblastomas
3. Pancreatic cyst and endocrine tumor
4. Pheochromocytomas
5. ccRCC
6. Epididymal cystadenomas
7. Endolymphatic sac tumor : located in the posterior area of petrous bone and
frequently involve the dura (present with hearing loss)
• Defective VHL gene account for 60% of sporadic RCC
7
8. Mx of VHL
• Multiple RCC in kidney after 20yo
• If lesion > 2-3cm increase risk of malignancy
• FU if see lesion > 2cm :
– Annual USG
– CT/MRI when cyst > 2cm (6-12monthly)
• Mx:
– NSS is the aim
– Cryo, RFA or HIFU for small lesion < 3cm
– PN for lesion > 3cm
– RRT if anephric
8
25. Important physical finding
• Cervical LN
• Palpable abdominal mass
• Non reducing varicocele
• Bilateral LL edema (venous involvement)
25
26. Lab test
• CBP: Anemia , Plt , neutropenia
• Serum Cr / GFR (esp bil tumors)
• CRP/ ESR
• ALP
• Corrected serum Ca
• Isotope scan
• 24 hr urine
26
27. Separate renal fxn
• When solitary kidney or bilateral tumors
• When RFT compromised
• Patient with co-morbid disorder with risk of
future renal impairment (DM, chronic
pyelonephritis, renovascular disease ,
stone, renal polycystic disease)
27
28. Radi Investigation
• USG as screening
• Doppler USG: venous extension
• CT: Primary tumor extension, LN , adrenal extension ,
morphology of contralateral kidney, metastasis (liver)
• MRI: Local growth, IVC involvement
• Contrast enhance USG: tumor thrombus
• CT angiogram: vascular anatomy
• PET: remain to be determine
• To differentiate solid or cystic
– If cystic : Bosnik Classification
– If solid : presence of enhancement
28
29. CT
• Enhancement in renal mass: change in >20 HU strong evidence
of enhancement
• But poorer enhancement than surrounding parenchyma
• Absence of fat content (vs AML)
• CT phase:
1. *Pre-contrast phase: 3-5mm slide with overlap to reduce partial
volume effect
2. Iodinated contrast (50-100ml @ 150-300mg/ml Iodine rapid IV)
3. Cortico-medullary phase (30-70s): good for vessels
4. *Nephrographic phase (70-180s) : optimum depiction of renal mass
that do not enhance to the same degree as renal parenchyma
5. Excretory phase (10-20min): for collecting system
• Isodense but enhancing: Pseudotumor hypertrophied cortical
column (of Bertin) or dysmorphic segment
• Provide information on:
1. Function & morphology of contralateral kidney
2. Primary tumor extension + extrarenal spread
3. Venous involvement
4. Local LN enlargement
5. Adrenal gland and liver 29
31. Precautions before CT
• Drugs-particularly metformin/nephrotoxic
drugs
• issue of contrast nephropathy
• address contrast allergy
31
32. Metformin
• Guideline from European Society of Urogenital
Radiology
1. if serum creatinine: normal
• stop metformin (at the time of exam until 48 hours
passed and serum Cr remain normal)
1. if serum creatinine: impaired
• stop metformin 48 hours before exam, resume
metformin 48 hours later if serum Cr remained at pre-
exam level
1. if contrast given to patient taking metformin
• metformin stopped immediately
• hydration to ensure U/O 100ml/hr x 24 hours
• monitor serum Cr, lactic acid and blood gas
32
34. Contrast nephropathy
• Definition:
– 25% increase in serum Cr , or at least 44umol/L
– During 3 days after contrast administration
• Mechanism:
– Direct toxic effect on tubular cells
– Vasoconstriction:
• High osmolar content induce marked natriuresis and diuresis
• Trigger tubulo-glomerular feedback response with constriction of glomerular
afferent arterioles
• Resulting in decrease in GFR
• Risk factor:
1. Age > 70
2. Renal impairment
3. DM
4. Dehydration
5. Congestive heart failure
6. Concurrent treatment with nephrotoxic drugs
34
35. • To minimize risk:
– Stop nephrotoxic drugs if any
– Adequate hydration
– Adminstration of N-acetylcesteine: 600mg BD
35
36. Contrast allergy
• Really allergy?
• Anaphalactoid reaction:
– Idiosyncratic reaction unpredictably and independently of
dosage and concentration of the contrast media
• Related to ionic and high osmolar content of the contrast
• Leading to release of different mediators
• Chemotoxic
– Severity related to dosage/concentration of contrast media
– Also related to characteristics of the agent
• Prevention:
– use low molecular non-ionic contrast medium
– Corticosteroid
36
37. Metastatic workup
• Chest CT most accurate for chest staging
• At least CXR
• Bone scan/ CT brain: only if symptom
37
38. PET in RCC: primary diagnosis
• Diagnosis
– FDG
• Increased background activity of healthy renal tissue and normal FDG
excretion in urine can make visualization of primary renal cancers by
PET difficult
• Not useful in primary diagnosis
• Low sensitivity as compared to CT (60% vs. 91.7%)
Kang et al 2004
– FMISO (fluoromisonidazole)
• F-FMISO, recognized non invasive method for detecting hypoxia in
18
tumours
– RCC is regarded as resistant to treatment with radiation and
chemotherapy
– May be due to malignant hypoxic areas in the tumour.
• Mildly increased uptake in some but not all histologically confirmed RCC
Lawrentschuk et al (2005)
38
39. PET in RCC: nodal staging and
metastasis
• Nodal status
– Highly specific for retroperitoneal lymph node metastasis
by using 18F-FDG
• PET was 75% sensitive and 100% specific
• (92.6% sensitivity and 98.1% specificity for abdominal CT)
Kang et al (2005)
• Distant metastasis
– Bone
• High sensitivity and specificity for bone metastasis
• Diagnostic sensitivity and accuracy of FDG-PET were 100% and 100%
• (bone scan sensitivity and accuracy were 77.5% and 59.6%,
respectively)
Wu et al (2002)
• 100% specificity for F-FDG PET for differentiating between benign
18
lesions and bone metastases
Kang et al (2004)
– Soft tissue
• PPV for metastases to soft tissue was 98.4%
39
Kang et al (2004)
40. PET in RCC: Summary
• 18
F-FDG
– Not useful for primary diagnosis because of urinary
excretion
– Certain role in staging and restaging disease when
evaluating especially visceral, lymph node and bony
disease
• As a complementary problem solving tool when conventional scans are
suspicious for metastatic RCC but equivocal
Kang et al (2004)
• Positive FDG-PET is predictive for the presence of metastatic RCC in
lesions imaged, may complement anatomic radiologic imaging
modalities, and may alleviate the need for a biopsy in selected
situations
Majhail et al (2003)
– Superior value of 18F-FDG PET over CT in the evaluation of
patients with suspected recurrent RCC
40
Ramdave et al (2001)
43. Bosnik classification
• Type I: Benign, smooth margin, no septation ,
calcification or contrast enhancement (no FU)
• Type II: Benign, hyperdense cyst < 3cm , smooth margin
,simple septation , minimal calcification , no contrast
enhancement (no FU)
• Type II F: Small risk of malignancy, hyperdense cyst >
3cm , mild thickening wall, hairline septae with minimal
enhancement ,nodular and thick calcification , no
contrast enhancement (FU)
• Type III: 50% malignant, thick irregular wall & septa with
contrast enhancement (surgery or FU)
• Type IV: clearly malignant cystic lesion with contrast
enhance soft tissue component (Surgery)
43
44. Proposed screening population
1. ESRF on dialysis
– Those with relative long life expectancy with no major co
morbidities
(Screening should start from the 3rd yr of dialysis)
1. VHL disease
– Biannual CT / USG from 11 yrs of age
– Periodic screening for extra renal manifestations
• Regular urinary catecholamines
• Regular ophthalmic exam
• Regular MRI CNS
• Regular auditory exam
– Should also consider genetic analysis in other family members
• 3. Other familial forms of RCC
• 4. Patients with tuberous sclerosis
44
50. Issues on Renal sinus fat
• RSF invasion carries a worse prognosis
then perinephric fat invasion
• Should be not be T3a
50
51. Adrenal invasion
• Adrenal invasion has very poor prognostic value
• CSS of pT3a/b with ipsilateral adrenal involvement
worse compare with pT3a/b that did not invade the
adrenal gland (p<0.001)
• No difference of pT3a/b + adrenal compare with T4
• RCC with adrenal invasion more aggressive then tumor
involve perinephric or renal sinus fat
51
52. Prognostic Factors
• Anatomical: TNM stage: size, venous invasion, capsule, adrenal, LN ,
Distance Met
• Histological:
– Fuhrman grade
– RCC subtype (chRCC >> pRCC >> ccRCC) [Patard JCO05]
– Sacromatoid features
– Microvascular invasion
– Tumor necrosis
– Invasion into collecting system
• Clinical:
– Pt performance status
– Localized symptoms
– Cachexia, anemia , Plt count
• Molecular : Carbonic anhydrase IX, VEGF, HIF, Ki67, p53, Phosphatase
and tensin homologue, E-cadherin , CD44
• No molecular markers can improve predictive accuracy of current prognostic
system, not for routine practice
• prognostic information provided by the RCC subtype is lost when stratified
to tumor stage
52
53. Cephalic extent of venous
thrombus
• Cephalic extent controversial
• Some reports suggest cephalad extent not of prognostic
value as long as tumor is otherwise confined
• Others reckon incidence of systemic / locoregional
progression higher with level III-IV VTT
• Novick and Glazer 1996
– 5yCSS 56% in 18 patients with thrombus up to RA
– All dealt with CPB + DHCA (the gold standard)
53
55. Nomogram
• Nomograms are statistical models specifically designed
to maximize predictive accuracy
• Based on a combination of variables that allow for a
more individualized prediction of outcome
• Superiority of more complex predictive modeling in
providing improved accuracy compared with risk group
assignment techniques (TNM, stage)
• A precise and punctual instrument to estimate the
prognosis of a single patient
• Concordance index (c-index) : a measure of the
predictive accuracy of prognostic algorithms
• CI = 1 (perfect accuracy), CI =0.5 (random chance)
55
56. Pre-op Prognostic model
• Pooled MKSCC and Mayo clinic (2517pt)
• Predict outcome of pt treated with nephrectomy
• Factors:
1. Size
2. Mode of presentation
3. LN
4. Necrosis on imaging
– Significantly associated with metastastic recurrence after nephrectomy
• Condrodance index of 0.8 [JU 2008]
56
59. Poor prognostic indicator
• MSKCC
1. Low Karnofsky performance status (<70)
2. Elevated LDH
3. Low Hb
4. Elevated corrected Ca
5. Time from initial dx to start of therapy > 1
year
59
64. UCLA- UISS (2001)
• Divided pt into 5 risk group
• Statistically significant difference in disease-specific
survival
• Base on tumor stage , nuclear grade , ECOG PS
• 82-86% accuracy
64
65. UCLA- UISS 2002
• Stratified pt into: low, intermediate , high risk group for disease progression
• Predict 1-5 CSS & OS
• For non metastasis and metastasis disease
• Does not predict probability for individual, group instead
• Fully validated : accuracy 73%
65
66. Mayo SSIGN score (2002)
• Pt with cRCC (>1800)
• Score based on: TNM, size, nuclear
grade, presence of necrosis
• Estimate cancer specific survival (1-10yr)
• Has not yet been validated internally or
externally against additional database
• CI: 0.833
Frank , JU 2002
66
68. Which one is most accurate?
• 2404 record, 6 countries
• Compare : Kattan, UCLA-UISS, Yaycioglu (pre-op), Cindolo (pre-op) model
• Discriminating ability by Harrel c-index
• Result:
– All model discriminated well (p<0.0001)
– CI : Kattan (0.7), UCLA (0.68), Yaycioglu (0.59), Cindolo (0.615)
• Conclusion: post-op predictive model better then pre-op
• Kattan model was most accurate, follow by UCLA
• Katten model can be useful in UISS intermediate risk patients
Cindolo , Cancer 2005
68
69. Molecular prognostic model
• CA-IX: marker for response to systemic therapy (high CA-IX high
response to IL-2), but dose not predict response to temsirolimus
• B7-H1: expression asso with 4.5x risk of CS mortality
• B7-H1 + Survivin: 2.8x CS death
• Fxn as inhibitor of T cell mediate antitumoral immunity blockade
with monoclonal antibody result in therapeutic response 69
76. Bellini duct carcinoma
(collecting duct carcinoma)
• Very rare type of RCC
• 40% have metastatic at
initial presentation
• Most patients die within 1–
3 years from dx
• Largest case series (n =
81) outcome:
– At diagnosis : Regional
lymph node metastases
(44%) distance metastases
(32%).
– Survival rate : 48% (5 yrs) &
14% (10 yrs)
76
77. • Sarcomatoid RCC:
– High-grade transformation in different RCC types,
without being a distinct histological entity. Worse
prognosis
• Renal medullary carcinoma:
– Devastating malignancy, extremely rare
– Young men with sickle cell trait.
– 2% of all primary renal tumors in 10-20yo
– 95 % present with Metastatic disease
• Unclassified RCC:
– Diagnostic category for RCC that cannot be assigned
to any other category of RCC-type carcinoma
• Papillary adenoma:
– Tumors with papillary or tubular architecture
– Low nuclear grade and < 5 mm in diameter
– only found incidentally in a nephrectomy specimen
77
78. Multilocular cRCC (multilocular
cystic RCC):
– There are no strict histopathological criteria
– In the WHO 2004 classification , multilocular cRCC is an
independent entity, but it is essentially a well-differentiated
cRCC.
– 3.5% of surgically treated kidney tumors
– Metastases of this tumour have not been described
– Bosniak classification, presents as a Bosniak type II or III cystic
lesion
– This type of Bosniak lesion can also be due to a mixed epithelial
and stromal tumour of the kidney (MESTK), a cystic nephroma,
or a multilocular cyst, all benign lesions.
– Pre-operative biopsy and intra-operative frozen-section analysis
does not lead to a correct diagnosis.
– All these tumours are treated with the same operative strategy.
– If technically feasible, a nephron-sparing procedure is the
procedure of choice for a complex multicystic renal mass with
enhanced density is observed
78
79. • Translocation carcinoma
– uncommon tumours, children & young adults.
– 90% involve the transcription factor E3 (TFE3) located on Xp11.2
– At an advanced stage at presentation , but relatively indolent course
– Another rare group of RCCs : translocation (t (6; 11) (p21; q12)) has
also been reported
• Mucinous tubular and spindle cell carcinoma
– Associated with the loop of Henle.
– behave in a low-grade fashion
• Metanephric tumours
– 3 types: 1) metanephric adenoma,2) adenofibroma, and 3)metanephric
stromal tumour.
– Very rare benign tumours and surgical excision is sufficient
• Renal epithelial and stromal tumours (REST)
– a new concept that brings together two benign mixed mesenchymal and
epithelial tumours: 1) cystic nephroma and 2) mixed epithelial and
stromal tumours
– Imaging REST cystic lesions : Bosniak type III
– Consider to be benign and surgical excision as curative
79
80. Carcinoma associated with ESRF
• Cystic degenerative changes (acquired cystic kidney disease [ACKD]) and a higher
incidence of RCC are typical features of ESKD (end-stage kidney disease).
• Incidence of ACKD : 50% in patients undergoing dialysis, but also depends
– on the duration of dialysis
– gender (3x more common in men)
– diagnostic criteria of the method of evaluation.
• RCCs of native end-stage kidneys : 4% of patients.
• Lifetime risk of developing RCCs : > 10 times higher than general population.
• RCC in ACKD is characterized by :
– multicentricity and bilaterality
– found in younger patients (mostly male)
– less aggressive behavior.
• It is usually quite aggressive in transplanted patients (immunosuppression)
• Histological spectrum similar
– Predominant form is pRCC, 41-71% of ACKD-associated RCC vs 10% in
sporadic RCC.
– The remaining tumours are mostly cRCC
• 2 new renal tumor associated with ESKD: [Tickoo et al]
– 1)acquired cystic disease-associated RCC‘ and
– 2)‘clear-cell pRCC‘.
– These entities have not generally been accepted..
• Patients with ESKD should undergo an annual ultrasound evaluation of the kidneys
80
82. Oncocytoma
• Benign tumors
• 3-7% of all renal tumors
• Presentation: incidental , rarely loin pain or hematuria
• Imaging appearance:
– Imaging characteristics alone are unreliable to differentiate from
RCC
– Central stellate scar in CT or MRI
– Spoke-wheel pattern of feeding arteries on MRA
• Gross:
– Well –circumscribed, homogenous, tan color lesion
– Central stellate scar (entrapped tumor cells exhibiting focal
cytoplasmic clearing
• Histology:
– cells with deeply eosinophilic cytoplasm packed with
mitochondria originate from intercalated cell of the collecting
ducts
– EM: cytoplasm loaded with mitochondria (cytoplasmic
eosinophilia, brown) 82
83. • Genetics:
– loss of chromosomes Y and 1,
– Translocation of chromosome 11
– Heterozygosity on C 14q
• Pre –op percutaneous biopsy : low specificity ,
oncocytotic cells are also found in
– cRCC (granular-cell variant of RCC)
– Eosinophilic variant of chromophobe RCC
• ‘Watchful waiting’ : selected cases of
histologically verified oncocytoma (level of
evidence: 3)
• After nephrectomy: no need to FU as benign
83
84. AML
• 1% of surgically removed tumor
• benign mesenchymal tumor composed
1. Adipose tissue
2. spindle and epitheloid smooth muscle cells,
3. abnormal thick-walled blood vessels.
• Sporadically (80%)
– 4x more likely in women, middle age
– 80% Rt side
– Growth rate 5% per year
• In tuberous sclerosis (20%)
– F: M = 2:1 , 30yo
– multiple, bilateral, larger
– Growth rate 20% per year
– likely to cause spontaneous hemorrhage
84
85. AML
• Presentation: incidental (50%), loin pain , mass , hematuria
• Massive retroperitoneal bleeding (10%): Wunderlich’s syndrome
• Dx
– USG: bright echo- pattern without acoustic shadow (vs stone)
– CT and MR imaging: presence of adipose tissue (low HU -20 to 0)
– Biopsy is rarely useful. Difficult to differentiate between tumours
composed predominantly of smooth muscle cells and epithelial tumours.
• Epitheloid AML is a potentially malignant variant of AML
• Complications:
– retroperitoneal bleeding
– bleeding into the urinary collection system
– Bleeding tendency : irregular and aneurysmatic blood vessels
• The major risk factors for bleeding :
– tumour size (>4cm)
– the grade of angiogenic component of the tumour
– Presence of tuberous sclerosis
85
86. • Primary indications for intervention
– Symptoms such as pain, bleeding or suspected
malignancy.
• Prophylactic intervention is justifiable for:
1. large tumors (the recommended threshold is≥ 4 cm)
2. Females of childbearing age
3. Patients in whom follow-up or access to emergency
care may be inadequate
• Surgery: Most cases NSS, some RN
• Others: selective arterial embolisation (SAE)
and radiofrequency ablation (RFA)
• Although SAE is effective at controlling
haemorrhage in the acute setting, it has limited
value in the longer-term management of AML
86
87. Angiomyolipoma
• “Oesterling and coworkers (1986) reported
that 82% of patients with AMLs larger than
4 cm in diameter were symptomatic, with
9% in hemorrhagic shock at the time of
presentation; in contrast, patients with
smaller tumors were symptomatic 23% of
the time”
87
88. Tuberosis Sclerosis
• Genetic multisystem disorder characterized by widespread
hamartomas in several organs: brain, heart, skin, eyes, kidney, lung,
and liver
• Bilateral, multifocal AML; 1-3% had RCC
• AD with incomplete penetrance; 1 in 5,800-10,000
• Features:
– adenoma sebaceum / ungual or periungual fibroma / shagreen patch /
hypomelanotic macule
– retinal hamartoma / cortical tuber / subpendymal nodule or astrocytoma
– cardiac rhabdomyoma / lymphangiomyomatosis
• Affected genes TSC1 (9p34) and TSC2 (16p13.3) code for hamartin
and tuberin.
• TSC2 mutations more common than TSC1, esp in sporadic cases
(70-80%)
• The hamartin-tuberin complex inhibitis the mTOR pathway, thus
affecting cell proliferation and growth
88
89. • Diagnostic criteria : 2
major or 1 major + 1minor
clinical feature
• CNS complications occur
in 85% of TS patients :
– Mental retardation
– autism, behavioral problems
– epilepsy
•
• Cortical tuber,
subependymal nodule,
subependymal giant cell
astrocytoma
89
90. • Renal complications in TS
– Commonest cause of TS-related death
– AML occurs in 70-90% of TS
• 20% to 30% of all AMLs are found in patients with TS
• AML in TS patients (c.f. sporadic AML) :
– Mean age at presentation is 30 years
– Female-to-male predominance of 2:1
– Bilateral and multicentric
– Accelerated growth rates and symptomatic presentation
• Massive retroperitoneal hemorrhage from AML : Wunderlich's
syndrome
• Ref : Campbell v9 Chapter 47, Curatolo et al Lancet 2008; 372 :
657-68
90
91. New histological entities
• Thyroid-like follicular tumour/carcinoma of the
kidney
• RCC associated with neuroblastoma
• Renal angiomyoadenomatous tumour
• Tubulocystic carcinoma
• Clear cell pRCC
• Oncocytic pRCC
• Follicular renal carcinoma
• Leiomyomatous RCC
91
94. Small renal mass
• Growth rate
• Chance of being malignant
• Chance of metastasis
• Any predictor of benign of malignant tumor
94
95. Natural History
• Bosniak and associate in 1996
– 72 small renal tumors (<3.5cm) in 68 pt
– FU interval 2-10 years (mean 3.3 years)
– Tumor characteristics:
well marginated, homogenous solid
tumors
– Tumor growth rate:
• median growth rate 0.36cm/year
• no metastasis
– 32 tumors >3cm excised
• all were stage I RCC 95
96. Natural History-Results from Meta-
analysis
• 234 renal lesions from 9 institutions
undergo a period of active surveillance
– overall combined mean size 2.6cm (1.73-
4.08cm)
– mean Fu duration 34 months
– mean growth rate 0.28cm/year (0-1.76cm)
• Chawla SN, Uzzo RG.The natural history of observed
enhancing renal masses: meta-analysis and review of the
world literature. J Urol 2006
96
97. Pathology of Active Surveillance
Series
• In Chawla meta-analysis
• 46% of pathology was available
• 92% were malignant (reflect selection bias)
– clear cell (>90%)
– 9% (papillary)
• grading available in 76%
– low grade more common (again reflect selection bias)
• Lesion size at presentation did not predict the overall growth rate
• Progression to met disease was identified in only 1% of lesions
• Conclusion : surgery remain standard of care
97
98. Predictor of Malignancy:
size related
<1cm 1-2cm 2-3cm 3-4cm
Analysis of 2935 nephrectomy specimens in Mayo Clinic
Frank , et al: Solid renal tumors: an analysis of pathological features related to
tumor size. J Urol 170. 2217-2220.2003; 98
99. Correlation of growth rate and
malignancy
• Most series confirmed lack of growth does not
correlate with benign pathology
• Largest one from ‘zero growth’ study: Uzzo
Ju2007
– 106 enhancing renal mass observed for 29 months
– 33% had zero net growth
– likelihood of pathologically confirmed RCC were identical
in ‘zero growth’ and ‘active growth’ groups.
– no difference in
• Age
• Solid /Cystic appearance
99
100. Growth rate of
Benign and Malignant lesions
• No difference in Growth rate
– comparing benign lesions (oncocytomas) and
RCC
• Chawla SN, Uzzo RG.The natural history of observed
enhancing renal masses: meta-analysis and review of the
world literature. J Urol 2006
100
102. Any Predictors of Progression?
• symptoms?
• size of lesion?
• cystic or solid components?
• Pathology grading?
• Histological subtype?
102
103. Clinical Predicators of progression
• Symptomatic tumors tend to have more rapid
growth in a series of 22 patients
– 45ml/year v.s 16ml/year
• but no comparision of initial tumor size
• Sowery RD, Siemens DR.Growth characteristics of
renal cortical tumors in patients managed by watchful
waiting. Can J Urol 2004.
103
104. Symptom development
correlate with worse outcome
• Tumor related symptoms
– only 2 series in literature commented on
symptoms development
– most were haematuria
– onset of symptoms warrant consideration of
surgical removal
• associated with high grade/stage
• lower 10 year cancer specific survival
– Tsui KH,etal Renal cell carcinoma: prognostic significance ofincidentally
detected tumors. J Urol 2000
– Ou YC, Yang CR, Ho HC et al. The symptoms of renal cell carcinoma
related to patients’ survival. J Chin Med Assoc2003
104
105. Radiological Predictor
• Lesion size
– not correlate with growth rate in multiple
studies/meta-analysis
• Cystic and solid components
– cystic component tend to have better prognosis
• but not consistently predict a slower growth rate
• Still no reliable radiographic variable to
predict growth
105
106. Pathological predictors
• Nuclear grade
– association between nuclear grade and tumor
growth is not consistent
• Histological subtypes
– disease progression appeared to related to tumor
histology
• More favourable in chromophobe and papillary RCC
– but no study has investigated the kinetics of
different histological variant
• Molecular markers
– still at the stage of experiment 106
107. Any Predictors of Progression?
symptoms
?Histological subtype (may be)
X size of lesion
X cystic or solid components
X Pathology grading
107
108. How common is tumor metastasis
for small renal tumor?
108
109. Morbidity of observation-metastasis
• progression into metastasis is very rare
– in pooled analysis of 286 patients, only 3
progressed to metastasis (~1%)
– baseline size and growth rate were not predictive
– all were symptomatic at progression (haematuria)
• Chawla S.N, et al: The natural history of observed enhancing renal masses: meta-
analysis and review of the world literature. J Urol 175. 425-431.2006;
• Sowery R.D., Siemens D.R.: Growth characteristics of renal cortical tumors in patients
managed by watchful waiting. Can J Urol 11. 2407-2410.2004; Abstract
• Lamb G.W, et al: Management of renal masses in patients medically unsuitable
for nephrectomy—natural history, complications, and outcome. Urology 64. 909-
913.2004;
• Crispen P.L., Uzzo R.G.: The natural history of untreated renal masses. BJU
Int 99. 1203-1207.2007
109
110. Reasons of apparently low rate of
metastasis
• relatively short duration of Follow up (~2-3
yrs)
• presence of benign disease because of
selection bias (small homogenous tumors)
• treatment of growing lesions
110
111. Limitations & Pitfall
• most were small retrospective series from single
institutions
• significant selection bias
– tend to include small, well marginated and homogenous
renal mass
• significant proportion of these tumors are benign
• pathological evaluation not available in all
patients under observation
• series usually contained subpopulation of patients
with aggressive tumors
– e.g. 25% of masses doubled in size in 12 months in
Volpe’s Series 2004.
111
112. Active Surveillance
• Delaying treatment for evidence of
progression
• Rationale:
– significant proportion were benign disease ~20%
– even for RCC
• slow growth rate in short-medium term
• low potential to metastasize
• delayed management does not appear to compromise
survival or increase surgical morbidity
– many RCC occurred in mainly elderly
• risk of peri-operative morbidity is higher than
progression of tumor
112
113. Common Indications
for surveillance
• multiple co-morbidities
• patient’s choice
• fear of the potential need of renal
replacement
• tumor in solitary functioning kidney
/bilateral renal tumors
113
114. Concerns
• results from literature are subject to
selection bias
– application in young fit patients can be
dangerous
• awaiting studies to confirm the safe use of
active surveillance
• factors that trigger discontinuation of
surveillance remains to be established
114
115. small renal mass in elderly
• FU on 537 patients >75 and renal tumor <7cm for ~ mean
3.9 years
– examine overall survival
• Death rate 28%
– cardiovascular mortality most common (28%)
– death from tumor progression 4% only
• Multivariate analysis (predictor of survival)
– age, comorbidity but not management type
• predictor of cardiovascular mortality
– renal function and comorbidity
– nephrectomy is associated with greater loss of function
Lane Br etal. Cleveland clinic.Active treatment of localized renal
tumors may not impact overall survival in patients aged 75
years or older.Cancer. 2010 Jul 1;116(13):3119-26. 115
116. Active surveillance--Messages
• Most lesion dx nowadays are < 3cm (80%)
• > 80% of SRM are malignancy [Chawla]
• Most lesions grow slowly (0.3cm/year) [Chawla , Bosniak]
• Morbidity and progression to metastasis appeared low (1%) [Chawla]
• And death due to tumor progression for pt on surveillance is low (4%) [Lane
2010]
• It seems that AS may be acceptable
• Still, there is no reliable predictors whether tumor is malignant or tumor will
progress
– Only size correlated to chance of malignancy (but not growth rate, age or features)
– Only symptoms correlated to progression (but not size, features or grade)
• Thus even for SRM : treatment is justified (don’t know how to monitor)
• However, AS is still advocated in certain situation (see above)
• Surgical intervention can be safely deferred in short and medium term.
• Active Surveillance is safe in elder patients with multiple co morbidity and short
lifespan
– should be initiated with caution, particularly in young/fit patients
• Triggering point for surgery is still at the discretion of urologist.
116
117. Campbell 9th ed
• Patient with small, solid, enhancing, well-marginated, homogeneous
renal lesions, who are elderly or poor surgical risks, can safely be
managed with observation and serial renal imaging at 6 months and
1 year interval
• BUT this approach is not appropriate for patients with larger (>3cm),
poorly marginated, or nonhomogeneous solid renal lesions.
• Observation is not advisable in younger otherwise healthy patients
with small, solid tumors that have radiological characteristics of
RCC
• follow up data of natural history of small renal masses is limited
and imaging can not predict the behavior of renal mass.
Generally, AS is only suitable for elderly or short life expectancy
patient
117
118. Role of renal biopsy
• Aim: to determine malignant and type
• Not routinely done because: PPV of imaging is
so high that a –ve bx result dose not alter
management
• Indication: only when it can avoid operation
1. Renal abscess
2. Lymphoma
3. Before ablative therapy
4. Before Systemic therapy without previous histology
5. Surveillance
118
119. • Advantage:
– Confirm dx
– Tumor subtype and grading (70% correct)
– Impact on change of management (60%)
• Disadvantage:
– Difficult to diff benign from low grade malignant disease
– Chromophobic RCC may mimic oncocytoma
– Chance of False negative due to sampling error (24%)
• Core biopsy: Higher sensitivity and specificity (>90%)
than FNAC series
• 10-20% insufficient sampling (sampling error)
• Both FNA and bx are safe
• Cx: seeding (< 0.01%), bleeding (2%), penumothorax
(1%), AV fistula , visceral injury
• Not recommended for larger renal mass scheduled for
nephrectomy
119
120. Treatment Options:
Factors Driving Decisions
1. Patient factors
– Age, comorbidity, critical anticoagulation, other
cancers
1. Kidney factors
– Renal function, status of contralateral kidney,
prior renal surgery
1. Tumor factors
– Size and number of tumors, location, symptoms
1. Physician factors?
– Experience, support personnel, available
technology 120
121. Choice of operation localized RCC
• 1st must decide Radical nephrectomy vs NSS ?
• Then : Open vs Lap ?
• Result of ORN ?
• Role of LRN ?
• Therefore:
– ORN vs OPN (role of NSS)
– ORN vs LRN (role of LRN)
– OPN vs LPN (role of LPN)
– Robotic
• Ablative surgery: Cryotherapy , RFA
121
122. Txn of Localized RCC
• Surgery is the only curative approach for
RCC
• RN +/- adrenalectomy +/- LND is the
reference standard for curative treatment
for localized RCC with normal fxn
contralateral kidney [Lam EU04]
122
123. Adrenalectomy
• Incidence of adrenal involvement is low & related to stage [UCLA
series]
– T1-2: 0.6%, T3-4: 8%, overall : 4%
– All adrenal metastases occurred in
• Upper pole (all low stage and 60% of high stage)
• High stage
• Multifocal tumors (30% of high stage RCC adrenal mets)
– CT is >90% in SP and SV in detecting these metastases
• Not indicated in:
– Pre-op staging (CT/MRI) show normal adrenal
– Intra-Op: no suspicious metastasis
– No direct invasion by a large upper pole tumor
• Indicated:
1. Pre-op CT show suspicious adrenal involvement
2. Tumor at upper pole
3. Tumor of high stage T3/4
4. Intra-op:
• Nodule within the adrenal gland
• Direct invasion of the adrenal gland by large upper pole tumor
123
124. LN dissection
• Reasons why routine LN dissection is not required:
1. Tumors metastasize through bloodstream and lymphatic
system with equal frequency.
2. Lymphatic drainage is variable
3. Even extensive dissection cannot be expected to remove all
possible site of metastasis.
4. RLND doest not improve long term survival
5. In modern series eg. UCLA Pantuck 2004 : no difference in
local recurrence rate (~3%) with or without LND
• When LND is required:
– LND limited to hilar region or palpable or CT detected for
staging purposes
– During cytoreductive nephrectomy: survival was longer who
underwent LND than those without [Vasselli (NCI)]
124
125. LN dissection
• There is no RCT with mature results published for this
area
• I would not separately perform LND because I believe
the staging accuracy is unlikely to be improved further by
a LND if the preop CT is negative
• However I would perform LND when
– There are obviously grossly enlarged LN – this is mainly for
staging purposes
– The patient is having cytoreductive nephrectomy in preparation
for systemic immunotherapy because retrospective series has
shown survival benefit (5 months longer)
125
126. Embolization
• No benefit before routine nephrectomy
• For symptom controlled in pt:
– Unfit for surgery
– Present with non-resectable disease
• Reduce inta-op blood loss before
resection of bone or vascular met
• Relieve pain in bone or paravertebral met
126
128. Radical nephrectomy: Robson
• Radical nephrectomy consists of
– Early ligation of renal artery and vein
– Removal of kidney outside the Gerota’a fascia
(25% of localized RCCs manifest perinephric
fat involvement)
– Excision of the ipsilateral adrenal gland
– Performance of a complete regional
lymphadenectomy from crus of diaphragm to
the aortic bifurcation
128
129. Contemporary Indications for
Open Nephrectomy
• Clinical T3b-c / T4 disease
• Size > 13 cm (T2b >10cm)
• Hilar / interaortocaval adenopathy
Hilar Encasement by Adenopathy Tumor = 16 cm
129
130. Approach: Transperitoneal
• Advantages
– rapid and excellent exposure of renal pedicle that allow early
pedicle control
– minimize chance of tumor thrombi from entering systemic
circulation
– able to inspect peritoneal cavity for evidence of metastasis
– able to deal with concurrent extra-renal disease that require
operation. (e.g Gallstone)
– kyphoscoliosis/severe pulmonary disease where retroperitoneal
approach is not suitable
• Disadvantages:
– not suitable in patients with prior history of multiple abdominal
operation
– difficulty in patients with obesity
– higher incidence of postoperative ileus and possible long term
intra-abdominal adhesion formation
130
131. Retroperitoneal Approach
• Advantages
– avoid contamination of peritoneal cavity, drainage is limited at
retroperitoneal space
– suitable in obese patient
– panniculus falls forward
• Disadvantages:
– exposure of renal pedicle is not as good as transperitoneal
approach
– unsuitable for patient with severe scoliosis
– unsuitable for patients with cardiopulmonary problems
– lateral position with flexion of table would decrease venous
return due to compression on IVC and dependent leg position
131
132. Lap Radical Nephrectomy
• Established surgical procedure
• 1st by Clayman in 1991
• Same retroperitoneal or intraperitoneal
• 10 yr LRN result: Gill
• 7yr LRN vs ORN: Gill
132
133. Lap Radical Nephrectomy
• Laparoscopic is the new standard of care for low-intermediate stage
RCC and select stage 4 (metastatic) disease
• Indications
– Renal mass not amenable to partial nephrectomy (T1b or T2 +/- T3a)
– Normal renal function
– Normal contralateral kidney
• Lap RN vs ORN
– equivalent cancer free survival rates
– same tumor control rate
– lower morbidity rate (blood loss)
– Shorter length of stay
– Less analgesic requirement
– Early return to normal activity
133
Colombo JR Urology 2008; Permpongkosol S J Urol 2005; Gill IS Cancer 2001
134. Lap radical nephrectomy
• Berger & Gill, J Uro 2009
– Long term result of LRN (mean FU 11yrs)
– 73 patients, 85% T1-2 RCC
– 10yrs OS 65%, CSS 92% and RFS 86%
– 14% metastasis at mean FU 67months
– Conclusion
• Long term oncological outcome of Lap radical
nephrectomy are excellent and comparable to those of
open surgery 134
135. Lap RN vs ORN
• Colombo, J Urol 2008
• Cleveland Clinic, Gill
LRN ORN
• 7yr OS 72% 84%
• CCS 91% 93%
• RFS 91% 93%
• No port site recurrence
• Literature review showed
– port site recurrence is very rare (< 10 cases reported)
• most did not use entrapment bag or spillage of urine
– incidence port site metastasis comparable to Abdominal wound scar
metastasis (0.4%)
135
137. Survival of patient is mainly stage dependent
Stage Cancer Specific Survival
T1a 90-100%
T1b ~90%
T2 70-80%
T3a 60-80%
Venous Thrombosis 40-60%
137
138. LRN vs ORN (1)
• Colombo , Cleveland clinic , Clinic 2007
– 88 pt (LRN 45, ORN 43)
– T1 and T2 tumor
– Similar oncological outcome
– 5 yr OS for LRN: 81%
– 6 yr OS for ORN: 79%
– CSS similar (90% vs 92%)
138
139. LRN vs ORN (2)
• Hemal, JU 2007
– LRN (41) vs ORN (71) , 5 yr result
– T2 with mean size 10cm
– No local or port site metastasis
– CS equivalent for both group
• Hemal , WJU 2007, result of LRN
T1a T1b T2
5 yr DFS 97% 84% 82%
CSS 97% 86% 82% 139
140. LRN vs ORN (3)
• Permpongkosol, JU 2005, 10 yr series
10 yr DFS CSS OS
LRN 94% 97% 85%
ORN 87% 89% 72%
T1 98% 98% 75%
T2 84% 95% 81%
140
141. Complication of LRN
• Intra/early post-op:
– Bleeding
– Wound infection
– Convert to open
– Damage to adjacent organ
– Chest infection , MI , CVA
– Cx of penumoperitoneum (gas embolism , impair
venous return thrombosis & resp)
• Catheter and drain complication
• Need of monitoring of recurrence and RFT
141
142. Nephron Sparing Surgery (NSS)
• WHY?
1. NSS has similar oncological outcome to Radical surgery and is
recommend for T1 (up to 7cm)
2. Less incidence of renal failure in the long term
• NSS not suitable for:
– >T2 (locally advance)
– Unfavorable location
– Significant deterioration of general health
• Shall have Lap /open RN
• Open is still consider as the GOLD standard for PN
142
143. What consist of NSS
• OPN & LPN
• Thermal ablation
– Cryoablation
– RFA
– HIFU
143
144. Partial Nephrectomy
• Indications and contraindications
• Oncological control (as compared with
radical nephrectomy)
– survival data
– recurrence
• Complications
144
145. Why the role of RN is challenged?
1. Stage & size migration : more < 4cm mass
2. Renal preservation is critical even in normal
contralateral kidney
3. Higher risk of CKD after RN for RCC
increased risk of cardiac events,
hospitalization and death [population study]
4. Possible late recurrence in contralateral kidney
limited options of salvage surg
145
146. Then what is the role of RN?
1. Primary tumor > 7cm
2. Replace too much renal parenchyma
3. Location not suitable for NSS (central)
4. Older pt whom risk of complex PN may
not be acceptable
146
147. Indication for NSS
• Absolute:
– Anatomic/fxn solitary kidney
• 8% temp dialysis, 4% permanent dialysis
– Bilateral synchronous RCC
• Relative:
– Unilateral RCC with reduce fxn of contralateral kidney
– Opposite kidney fxn affected by condition that may impair renal
fxn in the future (e.g Hereditary RCC, DM, HT, RVD)
– Pt with increase risk of second malignancy (VHL)
• Elective:
– healthy contralateral kidney with favorable anatomy
– Small tumor< 4cm , Peripheral exophytic , non hilar tumor
147
148. Contraindication for PN
• Size: only up to 7cm (EAU)
• Tumor control is unable to be achieved
– Multifocal disease
– Locally advanced disease (>T3/ N+)
• Unfavorable position (relative)
• Too much parenchyma replaced by tumor
(relative)
148
149. Why Preserve Nephrons?
• Possibly benign diagnosis (20% in SRM)
– Women 2x more likely to have a benign dx
• Better preservation of renal function after PN than RN (even in pt
with normal pre-op renal fxn) [Lau , Mayo Clinic 2000]
• Renal tumor patient are prone to have underlying KD:
– Older male : > 60
– Medical co-morbidities affecting renal fxn
– 90% have intrinsic kidney disease [Path study from Harvard Med
School]
• Morbidity of dialysis and chronic renal disease
– Radical nephrectomy is a major cause of CKD in elderly patients
– Progression to ESRF after nephrectomy
– CKD Increase incidences of CVD , Hospitalization and lead to death
(related to severity of CKD) HR 1-6 [Go AS, NEJM 2004]
– Up to 50% yearly mortality in elderly diabetics undergoing HD
– 5yr survival in severe CKD (Grade 4-5) only 30%
• Thus renal preserving strategies is most important in RCC patient
149
150. Evidence that PN preserves renal
function
• Mayo Clinic study from Lau 2000.
– patients undergoing radical nephrectomy more
likely as compare to PN
• proteinuria
• serum Cr >2ng/ml
150
151. Evidence that PN
preserves renal function
• MSKCC data by Mckiernan
– study patients matched for associated risk factors, e.g. DM/HT
– serum creatinine in PN group significantly better than RN
group
• 1.0mg/dL v.s 1.5mg/dL (statistically significant)
• Huang/Levy from MSKCC
– 3 yr probablity of freedom from new onset of chronic kidney
disease (GFR less than 60ml/min)
• 35% for radical nephrectomy
• 80% for Partial nephrectomy
– Multivariate analysis: radical nephrectomy is an independent
factor for new onset CKD
151
152. Evidence that PN
preserves renal function
• Mayo clinic study by Thompson 2008
– query in nephrectomy registry
• RN or PN for organ confined tumor less than 4cm
• overall survival evaluated in patient <65
• RN was associated with increased risk of death
– after adjusting for tumor histology and medical comorbidities
152
153. Benefit of NSS vs RN
1. Equivalent oncologic outcomes in those with tumors <4
cm, and probably some up to 7 cm
2. Avoid over treatment of benign lesion (20% of SRM)
3. Concerns of lateral contralateral kidney recurrence
4. Equivalent cost effectiveness
5. Better QOL
6. Peri-op morbidity similar to RN
7. Decrease overall mortality
8. No difference in survival
153
154. Who will benefit most from PN
• For those who need to preserve renal fxn
most
– Increase serum Cr
– Proteinuria , HT
– Low tumor burden (< 4cm , low stage,
solitary)
• Pre-op normogram to predict post-
nephrectomy renal insufficiency
154
155. Complication of OPN
• Higher than RN but still tolerable (Van Poppel, Eur Uro 2007 RCT)
• Renal failure (6%) and need of dialysis (3%)
– Tumor > 7cm
– Excision of > 50% parenchyma
– Ischemic time > 60min
• Urinary fistula : (7%)
– Risk decrease in elective indication and small lesion
– Risk increase in central or hilar location
• Bleeding: 2%
– Reactive
– Secondary
• Renal infection / abscess: 3%
• Re-operation 2%
• Mortality 2%
• NSS for ABSOLUTE rather than elective carries an increase complication rate and a
higher risk of developing locally recurrent disease, probably due to the larger tumour
size
• Risk of local recurrence after PN
– General literature: 0-10%
– Tumor <4cm: 1-3% [Cleveland clinic Uzzo 2001] 155
157. Radical vs partial nephrectomy
• Only 1 RCT (level 1b)
• Van Poppel, Eur Urol 2011
• EORTC 30904, clinically <=5cm, T1-2
NSS RN
268 vs 273
• OS same for RCC patient
• 10yr OS : 75 = 80%
• 10yr no progression > 95%
• Both method provide excellent oncological
result i.e. no recurrence / met
157
158. ORN vs OPN
• Lau et al , Mayo clinic 2000
• Matched comparison: 164 pt
• FU 10 years
• ORN vs OPN
• Results: No significant differences in
– OS
– CSS : 96% (RN) vs 92% (PN)
– Complication rate
– Metastastic disease
• PN have decrease incidence of CKD and
proteinuria
158
159. Oncological efficacy: OPN series
• Largest report from Hafez , Cleveland clinic , JU 1999
– 485 pt with sporadic RCC , review
– 91% for absolute indication
– 5-year OS: 81%, 5-yr CSS : 92%
– 10-year OS: 53% , 10-yr CSS: 80%
– Enduring oncologic efficacy
– CSS is better with pt with tumor <4cm (100%)
• Fergany, JU 2000 [Novick’s 10year series]
– 107 OPN, 90% for absolute indication
– 5yr CSS: 88% 10-yr CSS : 73%
– Preservation of Renal fxn : 93%
– Local /distant recurrence: 10%/ 28%
• Herr , JU 1999 [10 year series]
– Unilateral tumor, normal contrlateral kidney
– 10-yr OS: 93%
– 10-yr Metastasis free survival : 97%
159
160. NSS for ELECTIVE indications
• MSKCC Herr 1999
– 10yrCSS 97%
• Mainz group (25yr fu)
– 5yr CSS 99%
– 5yr CSS 97%
• Novick’s TNM series (Hafez 1999)
– Subgroup of elective NSS (N=45)
– All <4cm
– 5YCSS 100%
160
161. Predictors of better outcome
• Careful patient selection:
– Lower tumor burden: < 4cm , low stage,
solitary lesion
• 5 year CSS of patient fitting these criteria
is 100%
– Cleveland clinic series (Licht, 1994)
161
162. Open Partial Nephrectomy:
Why is 4 cm the cutoff?
• 185 PN vs. 205 RN:
– No difference in CSS between groups with tumors
≤ 4 cm
– < 5% local recurrence in the PN group
• 252 patients with renal tumors ≤ 4.0 cm
underwent PN vs RN
– No local recurrence after either procedure,
– no difference in disease specific, disease-free or
overall survival
Lerner et al. J Urol 1996; Lee et al 2000
162
163. Open Partial Nephrectomy:
Can it be done for 4-7 cm (T1b)?
• Patard , multicenter, JU 2004
• CSS or tumor recurrence: no difference between
patients treated with RN vs PN for tumors 4-7 cm
• Leibovich , JU 2004
• Comparable CSS and distant metastases free
Survival for PN vs RN for T1b tumor
• Thompson, J Urol 2009
– MSKCC & Mayo clinic, 5yr Fu
– 873 RN vs 286 PN, 4-7cm
– No difference in 5yr and 10 yr OS / CCS
79%/92% 57%/86%
• Probably can expand elective partial nephrectomy
to tumors up to 7 cm
• Favourable result only in high volume center
[Mayo, MSKCC, UCLA]
163
164. OPN: impact of +ve surgical margin
• Kwon , BJU 2007
– 777 OPN
– Recurrence: 4% for PSM vs 0.5% for NSM
• What happen if we survillence PSM
– 1/7 die of metastasis, 6/7 DF at 32 months
• Study with longer FU needed to determine
true significant of PSM
• Cleveland FU protocol:
– FU CT 3 months 6 monthly for 5 year
164
165. What is the current status of LPN?
• Clamping of the renal vasculature to
provide bloodless field
• Careful resection of mass with rim of
normal parenchyma
• Intracorporeal suturing to close the
collective system and repair of capsular
defect
165
166. Lap PN
• Altrenative to OPN in experienced hands and selected pt
• Depend on experience and comfort of surgery than
on oncoligcal guidelines
• Optimal indication: small and peripheral tumor
• Long term RFT depends on warm ischemic time
• LPN vs OPN:
– Longer Ischemic time [Godoy JU09]
– Higher Complication rate
– Higher need of temp/perm dialysis
– Less costly (reduce LOS)
– Similar 5 yr oncological outcome: LPN = OPN
• RaLPN : still undergoing evaluation
166
167. • LPN (771) vs OPN (1029) [Gill from Cleveland clinic, 2007]
• Multicenter study , Single renal tumor, <7cm
• Similar:
– CSS (99.3 % vs 99.2% at 3 yrs)
– Post-op RFT (97.9% vs 99.6% at 3mo)
• Compare to OPN , LPN has:
– Decrease OT time
– Decrease blood loss
– Shorter hospital stay
– Longer warm ischemic time (30min vs 20min)
– More post-op complication require additional intervention
– More Urological complications (9.2% vs 5% p=0.0006)
– 3x More postoperative hemorrhage (4.2% vs 1.6% p=0.0002)
• Note: OPN is a higher risk group , more malignant bias
167
168. LPN long term oncological outcome
• Lane , Cleveland clinic, JU 2007
– 56 pt, 5 year FU,86% T1a
– OS : 86%
– CSS : 100%
– On case of local recurrence (2.7%), no metastasis
• Permpongkosol , JU 2006
– OPN (58) vs LPN (85)
– 5-yr DFS : 91.4%
– Actuarail Survival rate: 93.8%
168
169. JU Feb 2010
• 2246pt , cT1 tumor , < 7cm
• Txn with OPN or LPN
• In patient complete 7 year FU
– LPN OPN
– T1a CSS: 95% 95%
– T1b CSS: 82% 96%
– Metastasis free Survival: 97.5% 97.3%
• Conclusion:
– LPN and OPN provide similar long term OS and CSS
in pt undergoing PN for T1 RCC
– Oncological outcome are excellence with 97%
metastatic free survival in both group
169
170. When will you chose OPN
• Centrally located tumor
• Tumor in a solitary kidney
• Predominatly cystic tumor
• Multifocal disease
170
171. • Benway , EU 2010
• Largest retrospective review, 4 center , 2006-2008
• 183 pt, mean FU 28m
• Result:
– Mean ischemic time: 24min
– PSM: 2.7%
– Major complication : 8%
– No recurrence , no derange RFT
• Conclusion:
– RaLPN is safe and efficacious approach for PN with advantage
of short ischemic time
– Similar morbidity to other approach
171
172. Renal ischaemic injury
• What is the upper limit of warm ischaemic time
for full renal recovery?
– up to 30min can be sustained with eventual full
recovery of renal function [Ward]
– > 30min , generally significant renal fxn loss (necrosis
in proximal tubular cells)
• Who are more likely to sustain longer warm
ischaemic time?
– Solitary functioning kidney
– Kidney with extensive collateral vascular supply (renal
arterial occlusive disease)
172
173. Renal ischaemic injury
• How to prevent?
1. Preoperative and intraoperation hydration
2. Avoidance of nephrotoxic drugs
3. Avoidance of hypotension during anesthesia
4. Avoid unnecessary manipulation or traction on
the renal artery
5. Mannitol before arterial clamping
6. Clamping of artery alone instead of both
artery and vein
7. Cold ischaemia if required
173
174. Cold ischaemia
• When is cold ischaemic required? Prolong
procedure
• Mechanism?
– Reduce energy dependent metabolic activity of
cortical cells
– Decrease breakdown of adenosine phosphate
– Optimal intra-renal temp according to canine study is
15 degree.
– In reality, 20-25 degree is a reasonable and practical
compromise.
– Animal and human studies showed that this level of
hypothermia can provide complete renal protection up
to 3 hours
174
175. What are the methods of Cold
ischemia?
• Surface cooling
– Usually with ice slush
– Keep kidney covered with ice for 10-15 mins
after renal artery occlusion
• To achieve adequate core cooling
• Intra-arterial cooling via renal artery
175
176. Solid Renal Mass
Open radical Laparoscopic Nephron-Sparing
nephrectomy radical Therapy
•IVC tumor thrombus nephrectomy
•Imperative
•Extensive adenopathy •No imperative
indications for NSS
indication for NSS
•T4 disease •Elective
•No indication for
•Extensive prior renal indications
open nephrectomy
surgery
NEXT 176
177. Nephron-Sparing Therapy
Partial nephrectomy Ablative therapy Expectant
Management
•Elderly
Open Laparoscopic Perc. Lap.
•1 or >1 tumor, cystic •Technology and •High comorbidity
personnel available •Small,
•Location (intrarenal or
central) •Age, comorbidities asymptomatic tumor
•Ischemia time >30-45m •Critical •Established slow
anticoagulation growth
•Prior renal surgery
•Prior renal surgery 177
178. Fu after nephrectomy
• Aim :
– assess complication and renal fxn
– Monitor for local recurrence (5%), contralateral tumor (5%) &
metastasis
• Risk of local or distant recurrence:
– T1 7%
– T2 20%
– T3 40%
• Individual protocol of FU according to Leibovich Score (Mayo
clinic)
– According to: T stage, N stage, size, nuclear grade , necrosis
– To assess the risk of metastasis up to 10 year
– Low risk: USG kidney + CXR
– Intermediate & high risk:
• Abd + pelvis CT for 5yr
• CXR for 5 yr 178
181. Alternative to surgery
• Active surveillance:
– No correlation btw local tumor progression and risk of
metastasis
– If progression offer treatment
• Embolization:
– No benefit before routine nephrectomy
– Control gross hematuria and flank pain in
nonresectable disease or unfit pt
– Reduce intra-op blood loss in resection of bone or
paravertebral met
181
182. Ablative therapy
• Percu: RFA, Cryo, Microwave, laser, HIFU
• Adv: reduce morbidity , outpatient therapy, for high surgical risk pt
• Indication: small , incidental , exophytic elderly, genetic predisposition ,
solitary kidney with high risk of renal failure after NSS
• Not for percutaneous: >3cm , hilum, near ureter or collecting system
• Absolute CI: coagulapathies, severe sepsis
• RFA and cryo mostly study with medium FU data
• Preparation: bx for histology (but pathology unknown in 40% RFA and 25%
cryo pt)
• Cryoablation vs RFA: [Uzzo Meta-analysis Cancer 2008]
– More likely to be Lap approach but with higher complication rate
– Better local tumor control rate
– Less recurrent tumor
– Less require repeat ablation
– Both recurrence rate are higher then NSS (4.6 , 7.9 vs 2.7%) [Weld 05)
– Similar cancer specific survival rate but poorer than surgery
182
183. Cryotherapy
• Mechanism:
– As low as -190 degree
– Exploiting Joule Thompson principle :
• Rapid gas expansion of compressed argon leading to ultracold condition
• Cellular damage through:
1. Ice formation initially at extracellular space
2. Extracellular fluid become hyper-osmotic
3. Fluid shift lead to intracellular dehydration (Desiccation trauma)
4. Continue rapid super-cooling lead to intracellular ice formation
5. Intracellular ice disrupts cell organelles and cell membrane
– Delay Microcirculation stagnation
– Occur at slow thawing phase
– Circulation arrest and cellular anoxia
– chronic inflammation and necrosis
• Approach: Open , Lap, Percu
• Lap: Anterior & lateral tumors, Percu: posterior /post-medial tumor
• Method:
– rapid freeze (Argon) and slow thaw (Helium) (extend ice ball 1cm beyond
visible tumor edge under USG)
– Double Free-thaw cycle (larger necrotic area) 183
184. • Indication;
– Small tumor< 3cm
– Non-hilar tumor/ exophytic cases
• Contraindication:
– Poor life expectancy < 1 year
– Tumor> 3cm
– Located in hilum or proximal ureter or central collecting system
• Adv:
– No need hilar clamping or renal warm ischemia
– Relative low complication rate, rapid recovery
– Able to monitor & target the area by real time USG
• Complications:
– hemorrhage (1%)
– vascular thrombosis
– ureteral stricture, urinary fistula (consider stenting in solitary kidney or central
tumor)
• Effect on renal function: minimal
• Monitor: MRI (day 1, at 3,6 and 12 months then annual)
– Decrease in cryolesion size (89% by 5 year, complete disappear in 73%)
– Hallmark of success: absent of enhancement in cryolesion on gadolinium
enhanced MRI
• Outcome inferior to PN because: old pt with morbidity, initial experience
184
185. Oncological outcome
• Cleveland clinic experience of Lap
cryotherapy in 56 patients (with
minimum 3 yr FU: Hegarty, JU 2006
– 75% decrease in cryolesion
– OS: 81% , CSS 98%
• RFA : Park , Cancer Control 2007
– Mean Fu 20 months
– CSS: 83-100%
185
186. • 80 Lap Cryo, minimum 5-yr FU
• 69% bx proven RCC
• MRI : day 1 , 3,6 &12 months than annual
• Bx at 6 months
• T1 tumor, mean size 2.3cm
• 5 local , 2 local + met , 4 metastasis
• 5-yr RF: 78% CSS: 95% ,OS: 83%
• 10-yr DSS 83%, OS: 84% (in bx proven RCC)
• Previous RN significant predictor for DFS and
DSS
JU March , 2010 186
187. Lap Cryo vs PN Systemic review
[EU2011]
• Both PN and LCA procedures are viable options for
management of patients with SRMs.
• Compared with PN, LCA results in a
– higher risk of local tumor progression
– Lower risk of perioperative complications (strongly influenced by
selection bias) and thus limited conclusions can be made
regarding true differences in complications between both
procedures.
• PN is therefore the gold standard for SRMs,but LCA may
be indicated in selected patients with significant
comorbidity.
• Balancing cancer control and patient morbidity will be
crucial for counseling the patient.
187
189. Radiofrequency
• Mechanism
– Monopolar alternating current of 400-500kHz
– High frequency alternating current flows from
needle electrode to target tissue
• Ionic agitation
• Heat related molecular friction
• Denature of cellular protein
• Melting of cellular membrane
• Goal: maintain target tissue at 50-100° C
– Adequacy of ablation is assessed by
temperature or impedance from RF generators
189
190. Radiofrequency
• suitable cases:
– small renal tumor less than 3cm
– Non hilar exophytic cases
• Advantages:
– No need for hilar clamping
– no renal warm ischaemia
– low complication rate, rapid recovery
• Disadvantages:
– The process of RFA itself cannot be actively
monitored in real time imaging
• though impedance can be measured.
190
191. RFA: result
• Levinson etal from Johns Hopkins: 5 yr
• reported outcome for 31 patients undergone RFA for RCTs
(mean 2 cm)
• mean follow-up of 61.6 months.
• Only 18 had pathologically confirmed RCC
• overall recurrence free survival rate was 90.3%.
• However, the overall survival rate was 71%
– most died of non-RCC comorbidities
• Complication rate: 21%
• 3 case series : 300pt
– Average FU 2yr
– Tumor control rate (no lesion in MRI) : 90%
• Long term data is need to confirm efficacy
191
192. HIFU
• Not FDA approved
• Adv
– No puncture to tumor
– Transcutaneous ablation of tumor
– No risk of haemorrhage or tumor spillage
• Disadv (Extracorporeal HIFU)
– Inadequate eradication due to acoustic complexity of
intervening structures and respiratory movements of
kidneys
– Inability to monitor treatment progression in real time
• Transducer is brought directly to the target by
laparoscopic HIFU (Klingler Phase I trial)
192
193. Problems with ablative therapy
• Lack of enhancement on MRI not equal to
no viable cancer
• Lack of pathologic dx after txn
• Inability to confirm complete tumor
clearance
• Salvage surgery after ablation is
challenging
• Success rate fall for tumor > 3.5cm
193
194. Comparing Thermal ablation with
PN
• Meta-analysis by Weld/Landman 2005
– higher local recurrence with cryoablation and RFA
• 4.6% and 7.9%, compared with 2.7% by PN
• Disadvantages:
– inferior oncological control
– poor definition of post ablation success
– lack of pathology diagnosis following treatment
– inability to confirm complete tumor kill
– salvage nephron sparing surgery after ablation can be
very challenging
194
196. Mx of local recurrence
• Mechanisms of local recurrence
– Incomplete resection in the first operation
– Occult multicentric disease
• Novick : overall mean rate of multifocality in RCC 15.2%
• Novick : in tumors <4cm the risk is ~5%
– Genuine recurrence of new focus in the renal remnant
• Surgical excision if not metastasis
• For post PN recurrence;
– Either further PN or RN
196
197. Special scenario
• Bilateral tumor
• Hereditary RCC
• Tumor in solitary kidney
• Centrally located tumor
197
198. Bilateral tumor
• Aim: maximum renal preservation NSS
• Bilateral staged operation
• Operate 1st on kidney with less complicated
tumor base on size and location (Cleveland
clinic) 1st PN then RN
• Exception : Larger tumor is locally advanced
• Advantage:
– Provide flexibility in planning contralateral operation
– Abrogated need for temp dialysis
• Other options: simultaneous op, ablation
198
200. • Bilateral RCC is an absolute indication for NSS.
• If NSS is precluded on one side, I would perform
the partial nephrectomy first followed by
contralateral radical nephrectomy in a staged
manner
• This sequence obviates the need for temporary
dialysis in the immediate postop period (if ATN
develops after NSS)
• Also provides flexibility when planning the
procedure on the opposite side (?)
200
201. Hereditary RCC
• Younger age, higher tumor burden, bilateral and multifocal disease ,
may harbour hundred microscopic tumor , local recurrence is
common after NSS
• NSS vs RN vs surveillance
• NSS: 1st line
– Give pathology information
– High local recurrence rate
– 5-yr CSS for VHL : 70-100%
– ESRF : 23% require RRT
• RN: eliminate risk of recurrence, overtreatment, hasten ESRF
• If bilateral RN consider subsequent renal tranplantation
• Ablation: for hx of NSS, impaired RFT (not for further hilar clamping)
,significant multifocal disease
• For recurrence disease:
– <3cm surveillance
– > 3cm NSS
– Do not monitor hereditary leiomyomatosis because aggressive
201
202. Tumor in Solitary kidney
• At least 20% of normal kidney must be spared to avoid ESRF
[Campbell 07]
• Still some require RRT : temporary (8%), permanent (4%)
• >20min of warm ischemic time lead to higher rate of renal failure &
dialysis [Thompson JU07]
• Lane ,Cleveland clinic , JU2008
– OPN (169) vs LPN (30) in solitary kidney
– Equivalent 3 mo RFT
– LPN has:
• Longer warm ischemic time (9min P<0.001)
• 2.54x higher post-op complication (p < 0.05)
• Higher rate of post-op dialysis (P=0.01)
• Conclusion:
– OPN is a better treatment approach for localized tumor in solitary
kidney who have high risk of renal failure
– Ablation is an alternative
202
203. Centrally located renal tumor
• Margin size has no effect on risk of recurrence as along as the final margin
is negative
• Hafez , JU 1998
– Solitary , unilateral , < 4cm tumor, txn with PN or RN
– No significant difference between central and peripheral tumor in terms of :
survival , tumor recurrence or long term RFT
– PN is more challenging for central tumor than for peripheral tumor (longer
ischemic time, more entering into collecting system)
• Frank, JU 2006:
– LPN for Central vs peripheral tumor
– Similar peri-op complication and median blood loss
– Central tumor has:
• Longer ischmia time
• Longer OT time
• Longer hospital stay
• LPN can be expanded to include central tumors
• OPN is still the better approach in most patients
• RN is a viable options if PN cannot achieved –ve margin, reconstruction not
feasible , expertise with PN not available
203
204. Adjuvant therapy
• Tumor vaccination might improve PFS of
patients undergoing nephrectomy for T3
renal carcinomas
• Need confirmation about the impact on
OS (level of evidence: 1b)
• No role of adj therapy post nephrectomy
other than clinical trial (Grade A)
• Cytokines and vaccines: no improvement
in survival
204
206. Introduction
• Prevalence of RCC with venous thrombus:
4-10%
• Presentation: 95% symptomatic
– Hematuria (35%)
– Incidental (23%)
– Flank or abd pain (17%)
– Abdominal mass (2%)
206
207. • Physical examination:
– Bilateral LL edema
– Varicocele of recent onset (Rt side)
– Dilated superficial abd wall veins
– Caput medusae
– Pulmonary embolus
– Proteinuria
207
208. Imaging
• To determine superior extent of tumor thrombus to
determine surgical approach
• MDCT: 75-100% accuracy
– Vascular enhancement on angiogram in 35-40% (Preop embolisation
helpful in these cases)
• MRI
– Non invasive
– 80% accuracy
– MRI can differentiate bland from tumor thrombus with gadolinium
contrast enhancement
– Reconstructed image: caval wall invasion & relationship to HV
• Vena cavography
• TEE
• Should be done 1 week before OT
208
210. Pre-op TKI
• Sunitinib: decrease tumor size up to 36%
• Shrink level IV tumor thrombus
[Karakiewicz EU2008]
210
211. Other pre-op preparation
• Cardiac consultation: CPBP
• Coronary angiography
• CT & MRI of brain : exclude brain met that
could bleed
• Bx + Neo-adj systemic therapy in case of
high burden of metastatic disease
211
214. Prognostic staging system
• TNM classification
– pT3b : below diaphragm
– pT3c: above diaphragm
• Robson staging system:
– All tumor extending into the IVC or renal vein
are classified as stage III disease
214
215. Neves and Zincke [BJU 1987]
• Level 0: thrombus in RV
• Level I (renal): Thrombus < 2cm from RV
• Level II (Infrahepatic) : > 2cm from RV
• Level III (Intrahepatic): involved HV but
infradiaphragmatic
• Level IV (atrial) : involve
supradiaphragmatic vena cava or atrium
215
217. Incision
• Midline + sternotomy
– For level III & IV thrombus
– Single incision with good access to IVC , Renal pedicel and
contralateral kidney
– Div: no good exposure to liver and retrohepatic IVC
• Subcoastal (Chevron)
– For any thrombus level
– Exposure to both renal pedicles
– Can extend to include sternotomy (CPB)
– Posterolateral exposure to kidney
– Div: significant post-op pain
• Thracoabdominal:
– Ideal exposure to retrohepatic IVC (excellent for level III)
– Div: throacic cx (hernia, phrenic n injury , pneumothroax)
• Frank:
– Limited access to IVC
– Only for level 0 right IVTT without IVC extension 217
218. Operative approach
• Level I: Transabd approach
– Cause partial vena caval obstruction
– Satinsky clamping of renal vein / infrahepatic vena
cava proximal and distal to thrombus and
contralateral renal vein before venotomy to remove
thrombus
– May need caval reconstruction with pericardial graft /
PTFE graft.
• Level II: Transabd approach
– Extensive vena caval dissection
– Lumbar vein ligation
– Ligation of small hepatic vein to caudate liver lobe
218
220. Operative approach
• Level III:
– Transesophageal echocardiography (TEE)
– Transabdominal / thoraco-abdominal
– Liver transplant techniques to expose the retrohepatic veins
– Application of suprahepatic clamping and Pringle’s maneuver to
avoid hepatic congestion and back bleeding (20mins)
– Veno-venous bypass or CPB + DHCA in selected cases
• Level IV:
– TEE
– Gold standard is CPB + DHCA
– Combined median sternotomy and abdominal incision
– Useful technique is cavo-atrial shunt (to ?avoid CPB) but may
require Pringle’s maneuver
220
222. General principle
1) Renal hilar exposure
2) Ligation of the renal artery
3) Successive occlusion of the IVC above the thrombus
first, then of the contralateral renal vein and, finally, of
the IVC under the thrombus
4) Opening of the vena cava
5) Nephrectomy and thrombectomy
6) Verification that no residual thrombus is attached to the
IVC
7) Fushing of the occluded segment with blood and
heparin during the vena cava closure, keeping the
cephalad vascular clamp in place to avoid emboli
8) Release of the vascular clamps.
222
223. CPBP
• Approach for level III & IV IVTT
• Continuous venous return & arterial output
during IVC occlusion
• Combine with DHCA for complete
bloodless field
• Risk:
– Stroke (6%)
– Peri-op mortality (22%)
223
224. Venovenous bypass (VVBP)
• For II, most III &
select IV thrombus
• Adv:
– No need
heparinization
– Decrease blood
loss
– Short OT Time
224
Editor's Notes
CPD:Surgical Therapy of advanced Renal Cell CA 8/20/97 dm File: surgical tx of adv. renal cel ca 8-18-97 on hard drive
Cytokine therapy was the mainstay of treatment for the past 20 years. The 2 agents commonly used were interferon alfa and interleukin-2. Response rates with both agents were on the order of 12%-13% for interferon and about 23% with high-dose interleukin-2. Response duration was short with interferon, and there were some occasional durable responses with high-dose interleukin-2, but the treatment with this latter approach was toxic, expensive, and required inpatient administration.[1] In either case, the outcome for both treatments for most patients was poor, with an average survival of about 1 year.