RENAL TUMOURS

RENAL TUMOURS
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai

Moderators:
Professors:
 Prof. Dr. G. Sivasankar, M.S., M.Ch.,
 Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
 Dr. J. Sivabalan, M.S., M.Ch.,
 Dr. R. Bhargavi, M.S., M.Ch.,
 Dr. S. Raju, M.S., M.Ch.,
 Dr. K. Muthurathinam, M.S., M.Ch.,
 Dr. D. Tamilselvan, M.S., M.Ch.,
 Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

Renal Tumours
INTRODUCTION
 Increasing incidence due to increased use of abdominal imaging for renal specific and
non specific complaints.
 Benign and malignant
 >70% of asymptomatic renal mass are simple renal cysts.
 Renal Cell Carcinoma – 3.8% of all new cancers; Median age of diagnosis: 64 years.
 90% malignant renal tumours  Renal Cell Carcinomas
 80% Renal Cell Carcinomas  Clear Cell Carcinomas
 Collecting duct carcinoma  <1%
3
Dept of Urology, GRH and KMC, Chennai.

Renal Tumours
BENIGN RENAL TUMOURS
 Simple renal cyst
 Selected complex renal cyst
 Papillary adenoma
 Cortical and metanephric adenoma
 Angiomyolipoma
 Oncocytoma
 Rare cystic nephroma
 Mixed epithelial stromal tumour
 Leiomyoma
4

Bosniak Classification
5

Renal Tumours - Benign
PAPILLARY ADENOMA
 <5mm, well circumscribed, uniform eosinophilic or basophilic cells with normal
cytoplasmic and nuclear architecture.
 Diagnosis is controversial.All solid renal epithelium derived mass are malignant unless
proved otherwise.
 Loss of Y chromosome, trisomy 7 and 17.
 IHC: ‘+ve’ for AMACR (Alpha Methyl Acyl Co~A Racemase)
6

ONCOCYTOMA
 Most common benign tumour that appears as an enhancing renal mass, and is presumed to
be RCC (Renal Cell Carcinoma).
 Origin: Intercalated cells of distal renal tubule.
 Increased incidence in young females (but more common in older age).
 Well circumscribed, mahogany or tan, homogenous with central stellate scar.
 Round or polygonal cells in nested pattern – highly eosinophilic  increased mitochondria.
 Loss of heterozygosity at chromosome 1 and chromosome 14
 DD: Chromophobe tumours and clear cell RCC with eosinophilic components.
 IHC: Vimentin ‘+ve’ ; Cytokeratin & Parvalbumin ‘-ve’.
 Hybrid oncocytoma, oncocytomatosis, malignant oncocytoma.
 Birt Hogg Dube Syndrome. 7

Oncocytoma
8

ANGIOMYOLIPOMA
 <10% benign tumours
 Thick wall, poorly organized blood vessels with smooth muscle and mature adipose tissue.
 ?hamartoma. Arise from perivascular epithelioid cells (PEComas)
 Expresses estrogen, progesterone and androgen receptors.
 Common in females (rare before puberty).
 30% AMLs arise in tuberous sclerosis patients; 50% tuberous sclerosis patients have AML.
 TSC1 – chromosome 9q ; TSC2 – chromosome 16p
 Spontaneous perirenal haemorrhage – pregnancy (Wunderlich’s Syndrome).
 Presence of fat (HU < -20, on CT)
 DD: Liposarcoma, fat containing RCC (calcification) and fat poor AML (MRI is diagnostic).
 IHC: HMB45 protein ‘+ve’ (Human Melanin Black); Epithelial markers ‘-ve’
 Medical management: MToR inhibitors – EVEROLIMUS 9

Angiomyolipoma
10

Renal Tumours – Malignant – Renal Cell Carcinoma
 Group of distinct subtypes derived from various parts of nephron.
 Distinct tumour biology and unique genetic basis.
 Primarily a surgical disease and cure is rarely seen without complete surgical excision.
 3-4% of all adult malignancies. 2-3% (RCCs) familial. Majority are sporadic.
 Incidence: Males>Females. Increased incidence: 50-70 years.
 Increased incidence of localized tumours (incidentalomas) and detection at younger age.
 Tumours presenting at younger age are more symptomatic, advanced, high grade and
of unfavourable histology.And lymphadenectomy is recommended.
11

ETIOLOGY
 Smoking and obesity – strong risk factors.
 Tobacco – 1.4 to 2.5 times increased incidence. Obesity – Increased ILGF-1, estrogen,
arteriolar nephrosclerosis and increased local inflammation.
 ESRD (acquired renal cystic disease)
 Hypertension, lead compounds, aromatic hydrocarbons, asbestos, cadmium and trifluoro
ethylene.
 NSAIDS, coffee.
 Retroperitoneal radiation
 Familial RCC
12

13

VON HIPPEL LINDAU DISEASE
 Autosomal dominant disease. 1:36,000.
 >50% are RCCs.
 Early age at presentation, multifocal, bilateral.
 VHL tumour suppressor gene located on chromosome 3p.
 Suppression or mutation of VHL oncogene  increased accumulation of HIF-2alpha
 upregulation of VEGF protein, VEGFR, EGFR, PDGF, TGF-alpha, GluT1. 
increased neovascularity, angiogenesis  RCC.
 HIF-1alpha inhibits tumourigenesis.
14

VHL Gene Mutation
15

CT-VHL
16

Tumour
Biology
17

WHO Classification – Renal tumours
RENAL CELL TUMOURS:
 Clear cell renal cell carcinoma
 Multilocular cystic renal
neoplasm of low malignant
potential
 Papillary renal cell carcinoma
 Hereditary leiomyomatosis and
renal cell carcinoma associated
renal cell carcinoma
 Chromophobe renal cell
carcinoma
 Collecting duct carcinoma
 Renal medullary carcinoma
 MiT family translocation renal cell
carcinomas
 Succinate dehydrogenase deficient
 Mucinous tubular and spindle cell
carcinoma
 Tubulocystic renal cell carcinoma
 Acquired cystic disease-associated
 Clear cell papillary renal cell
carcinoma
 Papillary
adenoma
 Oncocytoma
 Renal cell
carcinoma,
unclassified
18

Specimen of Clear Cell Carcinoma
 70-80% of all RCCs.
 Typically yellow, highly vascular.
 Have pseudo capsule.
19

Specimen of Clear Cell Carcinoma pT3a
20

Histopathology – Clear cell carcinoma. H&E stain
 Typically round or polygonal cells with abundant cytoplasm.
 Contain glycogen and lipids, which are dissolved in routine histological preparations giving clear cell
appearance.
 3-5% sarcomatoid features. 10% venous extension.
21

Renal Cell Carcinoma – Sarcomatoid differentiation
 1-5% RCCs. Poorly
differentiated.
 Spindle cell histology,
vimentin ‘+ve’, infiltrative,
poor prognosis.
 Median survival < 1 year.
22

Clear cell renal cell carcinoma showing extensive necrosis
following treatment with the antiangiogenic agent sunitinib.
23

(Left - IHC with anti-CD31) (Right – Luminal spaces with
necrotic tissue)
24

Papillary Renal Cell Carcinoma
 10-15% of all RCCs. (Chromophilic RCC).
 Consist of basophilic or eosinophilic cells arranged in papillary or tubular configuration.
 Commonly multifocal and bilateral.
 Type-1 more common. (Basophilic cells, scant cytoplasm, low grade nuclei).
 Type-2 more aggressive. (Eosinophilic, abundant granular cytoplasm, high grade nuclei).
 Type-1: Trisomy of chromosome 7 and 17. Loss of Y chromosome.
 Type-2: Mutations of C-met on chromosome 7.
TYPE 1
TYPE 2
25

Chromophobe Renal Cell Carcinoma
 5% CRCCs, derived from cortical portion of collecting duct.
 Typically appear as well circumscribed homogenous tan tumour.
 Picture 1: Contains admixture of chromophobic and eosinophilic cells. (Distinct cytoplasmic
borders, perinuclear halos and nuclear raisins – Plant cell appearance).
 Picture 2: Stains positive Hale colloidal Iron.
 Electron microscopic findings: Multiple microvesicles – contains mucopolysaccharides.
26

Collecting Duct Renal Cell Carcinoma (Bellini Duct CA)
 < 1%.
 Presents earlier in life with advanced stage.
 Consists of dilated tubules and papillary
structures lined by single layer of cuboidal
cells. (Cobble stone appearance).
 Deletion on chromosome 1q and monosomy of
chromosome 6,8,11,18,21 and Y.
 IHC: Low and high molecular weight
cytokeratin, ulex europaeus, agglutinin 1
reactivity. ‘+ve’ E-Cadherin
 Share common features with urothelial
carcinoma – may respond to chemotherapy.
 Renal medullary carcinoma – in sickle cell
trait.
27

UNCLASSIFIED RCC:
 Origin – not defined. Generally poor prognosis.
RCC ASSOCIATED WITH Xp TRANSLOCATIONS:
 TFE-3 gene fusions
 Well circumscribed tan yellow tumour.
 Clear cells with papillary architecture.
 IHC: Nuclear TFE-3.
 40% of paediatric RCCs, young adults, advanced stage, indolent course.
 Lymphnode mets. & recurrence common.
28

METANEPHRIC TUMOURS:
 Metanephric adenoma
 Metanephric adenofibroma
 Metanephric stromal tumor
MESENCHYMAL TUMOURS:
 Leiomyosarcoma (including renal
vein leiomyosarcoma)
 Angiosarcoma
 Rhabdomyosarcoma
 Osteosarcoma
 Synovial sarcoma
 Ewing sarcoma
 Angiomyolipoma
 Epithelioid
angiomyolipoma
 Leiomyoma
 Haemangioma
 Lymphangioma
 Haemangioblastoma
 Juxtaglomerular
cell tumor
 Renomedullary
interstitial cell tumour
 Schwannoma
 Solitary fibrous tumour
29

MIXED EPITHELIAL AND STROMAL TUMOUR FAMILY:
 Adult cystic nephroma
 Mixed epithelial and stroma tumour
NEUROENDOCRINE TUMOURS:
 Well differentiated neuroendocrine tumour
 Large cell neuroendocrine carcinoma
 Small cell neuroendocrine carcinoma
 Paraganglioma
RENAL HAEMATOPOIETIC
NEOPLASMS:
GERM CELL TUMOURS:
METASTATIC TUMOURS:
TUMOUR LIKE LESIONS:
 IgG4 related disease
 Xanthogranulomatous
pyelonephritis
30

Mixed Epithelial Stromal Tumours
31

Xanthogranulomatous Pyelonephritis
32

DESCRIBED ENTITIES NOT CURRENTLY IN WHO:
 Thyroid-like follicular carcinoma of kidney Transcription elongation factor B (TCEB1)
mutated renal cell carcinoma
 Renal cell carcinoma with smooth muscle stroma
 Renal cell carcinoma with anaplastic lymphoma kinase (ALK) translocation
 Renal cell carcinoma occurring in patients with prior neuroblastoma
 Eosinophilic, solid, and cystic RCC
 Biphasic squamoid alveolar renal cell carcinoma
 Chromophobe renal cell carcinoma with neuroendocrine and neuroendocrine-like
features
33

Fuhrman’s nuclear grade
GRADE NUCLEAR SIZE NUCLEAR
OUTLINE
NUCLEOLI
1 10 microns Round, uniform Absent or
inconspicuous
2 15 microns Irregular Small visible at
400x
3 20 microns Irregular Prominent
4 >/= 20 microns Bizarre,
multilobed
Prominent with
heavy chromatin
clumps.
34

35

CLINCAL PRESENTATION
 >60% are now detected incidentally.
 Asymptomatic and non palpable until locally advanced.
 Classic triad: Flank pain, Gross haematuria and Palpable abdominal mass is now rare.
(Too late triad).
 Bilateral lower extremity edema and non reducing varicocoele (IVC thrombus).
SYMPTOMS OF SYSTEMIC DISEASE:
 Persistent cough, bone pain, and haemoptysis.
 Cervical lymphadenopathy
 Constitutional symptoms like fever, weight loss and malaise.
36

Renal Tumours – Malignant – RCC – Clinical Presentations
PARANEOPLASTIC SYNDROMES
 10-20% of patients with RCC.
 Internist’s tumour.
 Elevated ESR – 55%,
 Hypertension – 37%
 Anaemia – 36%
 Cachexia and weight loss – 34%
 Pyrexia of Unknown Origin (PUO) – 17%
 Abnormal liver function (Stauffer’s syndrome) – 14%
 Hypercalcaemia – 5%
 Polycythemia – 3.5%
 Neuromyopathy and Amyloidosis – 3.2% and 2% respectively.
37

Renal Tumours – Malignant – RCC
SCREENING FOR RCC
 In general, may not be justified as a routine practice.
 Early detection  Increased chance of cure
 Maybe indicated in the following:
- Patients with ESRD.
- Patients with known VHL disease.
- Relatives of patients with VHL disease & other familial forms of RCC.
- Patients with tuberous sclerosis.
- Not justified in patients with ADPKD
 Screening is done with urine analysis, ultrasonogram and CT.
38

Staging TNM
39

RCC Staging (Robson’s)
40

Tumour thrombus levels
LEVEL 0
Thrombus confined within renal
vein.
LEVEL 1
Tumour thrombus extending into
renal vein. (within 2 cm from
ostium)
LEVEL 2
IVC thrombus below the hepatic
vein.
1 2
41

Tumour thrombus levels
LEVEL 3
IVC thrombus extending upto
hepatic veins.
LEVEL 4
Thrombus extending beyond the
diaphragm into Rt. Atrium.
3 4
42

PROGNOSTIC FACTORS FOR RCC
 Pathologic stage has proved to be the single most important prognostic factor.
 Tumour size .
 Nuclear grade and histologic subtype.
 The prognostic factors have been subdivided into clinical, anatomic, histologic and
molecular factors.
 Molecular factors are
- CA-IX (Carbonic Anhydrase – IX) – indicates good prognosis.
- HIF-1alpha – indicates good prognosis.
43

Prognostic factors - RCC
44

EVALUATION
 Thorough physical examination and
complete medical history.
 Lab evaluation including Hb and ESR.
 Metabolic panel including calcium,
creatinine, LFT and urinalysis.
 Ultrasonogram of abdomen/scrotum.
- Mixed echogenic mass.
- Solid or cystic mass.
- Colour Doppler – increased vascularity,
tumour thrombus.
- Contrast Ultrasound.
 IVU
 Arteriogram
 CT with/without contrast.
- Abdomen, Pelvis, Chest and Brain.
 MRI – venous thrombus
 Chest X-Ray
 Bone Scan
 Central renal mass – urine
cytology, ureteroscopy, biopsy
45

METASTATIC EVALUATIONS
 Chest X-Ray
 Liver Function Tests
 Systematic review of abdominal and pelvic CT or MRI.
 Bone scinti scan in patients with elevated alkaline phosphatase, bone pain and poor
performance status.
 CT – Chest – Pulmonary symptoms and abnormal chest X-Ray.
 PET Scan – good specificity, but sub optimal sensitivity.
 Biopsy of the primary tumour and/or potential metastatic sites.
46

Renal Tumours – Malignant – RCC – Evaluation
IVU
 Normal
 Mass effect on the collecting system.
 Distortion of renal contour
 Enlargement of a portion of the kidney.
 Poor or absent contrast excretion.
 Calcifications.
 3D’s – Distortion, Destruction and
Displacement.
47

Doppler Ultrasonogram
48

CT Urogram Contrast CT
49

50

51

Liver mets. (left) and IVC thrombus (right)
52

Bone mets. (left) and lung mets. (CT) (right)
53

RENAL ANGIOGRAPHY
 It’s role in evaluation of RCC – markedly
diminished.
 Maybe useful in guiding the operative
approach in solitary kidney (NSS).
 Maybe useful in angioembolization.
 CT/MRI Angiography – Gives better
information with less risk.
54

BIOPSY
 Abdominal imaging studies provide high diagnostic accuracy.
 Routine biopsy not required.
 To establish RCC in small renal mass to guide active surveillance and ablation strategies.
 In Bosniak type 3, to differentiate malignancy from inflammation
 In lymphomas, secondaries, sarcomas.
 In inoperable cases prior to systemic therapy.
 The specimen must be taken from the core of the mass.
55

MANAGEMENT
 RCC is primarily a surgical disease. Very limited role for radiotherapy and chemotherapy.
 Immunotherapy and target therapy have a role in adjuvant management for advanced disease.
56

Renal Tumours – Malignant – RCC – Management
PRINCIPLES OF SURGERY
 Nephrons sparing surgery is appropriate in small unilateral tumours – selected T1b
and T2a tumours and in uninephric state, renal insufficiency, bilateral renal mass and
familial RCC.
 Open, lap, or robotic surgery may be done.
 Regional lymph node dissection is optional and recommended for patients with
adenopathy on preoperative imaging or palpable nodes at surgery.
 If adrenals not involved, resection may be omitted.
 Special teams are required for extensive IVC involvement.
 Observation or Ablative techniques for T1 lesions who are not surgical candidates.
 Ablative techniques are associated with high local recurrence.
 Candidates for cyto reductive nephrectomy should have good performance status
and no brain mets.
57

TREATMENT OF LOCALIZED DISEASE
 Multiple management strategies are radical nephrectomy, partial nephrectomy, thermal
ablation, cryoablation, RF ablation and active surveillance.
 Partially nephrectomy is preferred wherever feasible.
 Radical nephrectomy predisposes to CKD, potentially associated with morbid
cardiovascular events and increased mortality rates.
 Larger renal tumours, stages T1b and T2 often have already replaced a substantial
portion of the parenchyma. So, with a normal contralateral kidney, the merits of partial
nephrectomy vs radical nephrectomy is debatable.
 Radical nephrectomy includes perifascial resection of kidney, perirenal fat, regional
lymph nodes and ipsilateral adrenal gland.
58

 In stage 3 disease, lymph node dissection does not provide therapeutic benefit, but
maybe done for staging a disease.
 Ipsilateral adrenalectomy should be considered in large upper pole tumours.
 Radical nephrectomy is prefer treatment for tumours that extend into IVC.
 Partial nephrectomy – indicated in situations where radical nephrectomy will render
the patient anephric or at high risk for dialysis.
 Patients with bilateral synchronous RCC – bilateral partial nephrectomy if feasible.
(Staged procedures can be done).
 Local recurrence after partial nephrectomy – 3-5%
 The majority of local recurrences after partial nephrectomy are undetected microscopic
multifocal RCC in the remnant.
 Nephrometry scoring systems like RENAL (Radius, Exophytic/Endophytic, Nearness
to hilum,Anterior/Posterior, Location to polar lines.) may guide treatment selection.
59

Radical Nephrectomy
60

Partial Nephrectomy
Cooling the kidney
Lower pole tumour
61

Partial Nephrectomy
62

Partial Nephrectomy
63

Partial Nephrectomy
64

 Thermal Ablative therapies: include renal cryosurgery and radiofrequency
ablation as an alternative to NSS in small renal masses.
 Both can be done percutaneously or through lap exposure – reduced morbidity and
rapid recovery.
 Long term efficacy not well established.
 The ideal candidates may be patients with advanced age, significant co-
morbidities, patients with local recurrence after previous NSS and patients with
hereditary renal cancer with multifocal lesions.
 Other new technologies like high intensity focused ultrasound (HIFU) and image
guided radiosurgical treatments (cyber knife) are under development.
65

 Active surveillance (AS) is indicated in the incidental discovery of SRMs in
asymptomatic elderly, poor surgical risk patients who are unable or unwilling to
undergo surgery.
 SRMs will grow relatively slowly (0.1-0.34 cm/y), with a relatively low rate of mets.
(1.2-2% in 2-4 years)
 Percutaneous renal biopsy maybe considered prior to AS.
 CT/MRI within 6 months of AS initiation to establish growth rate and yearly thereafter.
 In general, AS is not appropriate in larger >4cm, poorly marginated, non homogenous,
solid lesions, when biopsy indicates aggressive RCC.
 AS also not advisable in younger, otherwise healthy patients.
66

 IVC involvement: seen in 4-10% patients with RCC.
 Suspected – lower extremity edema, isolated right side varicocoele, non collapsible
varicocoele, dilated superficial abdominal veins, proteinuria, non functioning kidney, and
pulmonary embolism.
 MRI – accurate modality for demonstration.
 45-70% can be cured with nephrectomy and thrombectomy.
 Level 1 and 2 thrombus can be managed with isolation of the involved vasculature and
thrombectomy.
 Level 3 and 4 require veno-venous or cardio-pulmonary bypass.
 Complete excision of the thrombus – good prognosis.
 Involvement of venous wall – bad prognosis. (complete excision may increase survival).
67

MANAGEMENT OF ADVANCED RCC
 Approximately 1/3rd of newly diagnosed RCC – synchronous metastatic disease.
 22-40% of clinically localized disease – eventually develop mets.
 Metastatic RCC – less than 5%, 10 years survival.
 Surgery – resectable tumours – radical nephrectomy if feasible.
- cytoreductive nephrectomy or debulking
- palliative nephrectomy
- metastasectomy – in solitary mets. (lungs)
 Improved survival in patients subjected to cytoreductive nephrectomy combined with
cytokine therapy (?target therapy).
 Palliative nephrectomy – relief of pain, haematuria, and paraneoplastic manifestations.
68

MANAGEMENT OF METASTATIC
RENAL CANCER
DR.ASHA VALANTINE L

 Approximately 1/3rd of all newly diagnosed  synchronous metastatic
disease
 20-40% of clinically localized disease at diagnosis  develop metastases
 Metastatic RCC is almost always fatal with 10 year survival rates of less than
5%
 Patients with metastatic disease account for majority of deaths related to
RCC
70

• Haematogenously via renal sinus veins, renal veins,
and venae cavae  pulmonary metastases
• Renal vein  lumbar veins  paravertebral venous
plexus  dural venous sinuses & pelvic veins 
CNS & osseous mets
• Lymphatic metastases can involve hilar, aortic, and
caval lymph nodes, and can enter the thoracic duct
or involve thoracic nodes directly.
71

LOCAL
THERAPY
SYSTEMIC
THERAPY
72

LOCAL THERAPY
• Cytoreductive
nephrectomy
• Embolisation of primary
tumor
Primary tumor
• Metastasectomy
• Radiotherapy
• Embolisation
Metastases
73

SYSTEMIC
THERAPY
Immunotherapy
Targeted therapy
Chemotherapy
74

75

RISK GROUP MEDIAN
SURVIVAL
Good ( 0 risk factors) 20 months
Intermediate (1-2 risk
factors)
10 months
Poor (3 or more risk factors) 4 months
76

 CURATIVE
 Tumor resection is curative only if all tumors are resected
 Primary tumor with single or oligo metastatic resectable disease
 PALLIATIVE
 For most patients to control sever local & systemic symptoms
 Requires systemic therapy
77

 In immunotherapy era with cytokines
 Increased long term survival with CN
 SWOG/EORTC Trial – OS improved by 11.1 months with CN+IFN alpha
 Targetted therapy era
 Doubtful benefit
 CARMENA TRIAL / SURTIME TRIAL
78

 Eliminate the primary source of immunosuppressive & growth promoting factors
 Removal of large primary tumors may provide clinical benefit
 Reports of spontaneous regression of metastatic lesions after nephrectomy
 Inhibition of Tcell function with large primary tumors  inability of systemic
agents (cytokines) to induce meaningful responses
 Prevents potential bleeding & pain from metastases during systemic therapy
 Accurate histologic subtyping
 Highly symptomatic tumor removed for symptom palliation 79

 OS (11.1 vs 8.1 months)
improved in CN+IFN alpha
80

 Good performance status (ECOG 0/1)
 Resectable primary tumor
 As palliative in
 Intractable pain, hematuria
 Constitutional symptoms
 Paraneoplastic manifestations
81

 Poor PS
 IMDC poor risk
 Small primaries & high metastatic volume
 Sarcomatoid tumor
 Confirmed by CARMENA
82

 Delay the start of systemic targeted therapy
 Perioperative complications coupled with disease progression
83

84

85

86

 Sequence of CN and sunitinib did not affect the progression free rate
at 28 weeks
 With the deferred approach,more patients received sunitinib and OS
was higher (although this finding was not statistically significant).
 Pretreatment with sunitinib may identify patients with inherent
resistance to systemic therapy before planned CN.
87

 Cytoreductive surgery should be offered to favorable risk group
 Metastatic RCC at presentation + good performance status + Resectable primary
+ low tumor burden outside the kidney  upfront CN is preferred
 For patients with limited tumor burden – metastasectomy rather than immediate
systemic therapy  associated with prolonged disease free survival in selected
patients
88

 Palliative
 Massive hematuria
 Flank pain
Unfit for surgery
Non resectable disease
89

 Do not perform cytoreductive nephrectomy (CN) in MSKCC poor-risk patients.
 Perform immediate CN in patients with good performance who do not require
systemic therapy / with oligometastases when complete local treatment of the
metastases can be achieved.
 Deferred CN with pre-surgical sunitinib in intermediate-risk patients with cc-
mRCC shows a survival benefit in secondary endpoint analyses and selects out
patients with inherent resistance to systemic therapy.
90

 Sunitinib alone is non-inferior compared to immediate CN followed by sunitinib
in patients with MSKCC intermediate and poor risk who require systemic therapy
with VEGFR-TKI.
 Offer embolization to patients unfit for surgery presenting with massive hematuria
or flank pain
91

 Higher OS & PFS for metastasectomy in Pulmonary,Liver & Pancreas
 Bone Metastases – Single dose IGRT 24 Gy/SBRT/EBRT
 Brain metastases – SRS / SRS+WBRT (better OS for SRS+WBRT)
 Embolisation
 Prior to resection of hypervascular bone or spinal mets – reduce
blood loss
 Palliative in painful bone mets
92

 Solitary metastatic lesion
 Age < 60 years
 Disease free interval of more than 1 year
 Pulmonary metastases (<4cm)
 Metachronous lesions
93

 Solitary brain metastases
 Metastatic lesions in weight bearing joints/bones
 Vertebral metastases with impending spinal cord compression
Surgical resection often combined with radiation and/or systemic
therapy
94

EAU GUIDELINES
With the exception of brain and possibly bone metastases,
metastasectomy remains by default the only local treatment
for most sites.
95

SYSTEMIC
THERAPY
Immunotherapy
Targeted therapy
Chemotherapy
96

 Interferon alpha
 Interleukin 2
 Immune check point inhibitors
97

• Spontaneous remissions have been documented.
• Increased risk of cancer in immunodeficient states
• Tumor infiltrating lymphocytes (TILs)
• Lymphocytes have been found within tumors.
• Isolated and expanded TILs have been the focus of experimental therapies.
98

99

 Was commonly the agent of choice in the initial treatment of
metastatic RCC until the advent ofVEGF pathway antagonists
 Response rate – 6-15%
 Decrease in tumor progression risk 25%
100

 Effective only in some patient subgroups
 ccRCC with favourable risk criteria
 Lung metastases only
 Bevacizumab + IFNalpha
 Increased response rates & PFS
101

5 MIU sc 3 days a week for 4 weeks
Wait for 4 weeks
Re-imaging
Response /
stable
Further course
Standard : 12 weeks
Maximum: 36 weeks
Progression Alternate systemic treatment
102

Acute toxicity
 ‘Flu like syndrome’
 Hypotension
 Renal abnormalities
Chronic toxicity
 Neuropathy
 Depression
 Hematological abnormalities
 Dermatological
103

 Recombinant human IL-2
 Patients with clear cell RCC appear most likely to benefit from IL-2
therapy.
 Lyophilized powder : 5 MU /vial
 Reconstituted with 1 ml of saline
104

 Response rate : 15-20%
 Complete regression of all metastatic tumor – 7-9% with high dose
IL2
 >80% of complete responder  disease free on long term follow up
 Unacceptably high treatment related mortality rate : 2-5%
105

 Only high dose IL2 regimens being considered for cytokine therapy
 Good performance status
 Limited metastases
 Time from nephrectomy to systemic therapy > 1 year
 Over expression of CAIX
106

 High dose - 6- 7.2 MU/kg q8h x 5 days IV bolus
 2.5 MU/day S.C / 5 days a week for 4 weeks
 Dose same as for INF alpha
107

 Hypotension
 Capillary leak syndrome
 Respiratory distress syndrome
 Neurologic (depression,confusion)
 Hepatic and renal abnormalities
 Cardiac (arrhythmias)
108

Death with IL-2 : 4%
Death with interferon : 0.74%
 Interferon is preferred over interleukin
109

 Combination of IL-2 and interferon resulted
 Higher response rate (18.6%)
 Higher 1-year event-free survival (efs; 20%)
 COMBINATION OF BOTH ARE NOT USED
 Due to toxicity
 No significant difference in survival
110

 The role of cytokine therapy in the current management of kidney cancer has changed with
the availability of novel inhibitors of VEGF and mTOR pathways,as well as immune
checkpointinhibitors with activity in clear cell RCC.
 Single agent interferon, once the standard in many institutions, is no longer used in
the treatment of clear cell RCC.
 However,given the inability of newer targeted agents to induce durable responses, high-
dose intravenous IL-2 remains a reasonable option in most carefully selected patients
with metastatic clear cell RCC
111

112

PD-L1/PD-1 & CTLA-4/B7
interaction inhibits immune
activation and reducesT-cell
cytotoxic activity
Maintains normal immune
responses and limits T-cell activity
to protect normal cells during
chronic inflammation
Tumor cells may circumventT-cell–
mediated cytotoxicity by
expressing PD-L1
113

ANTIBODY
AGAINST PD-1
ANTIBODY
AGAINST PDL-1
ANTIBODY
AGAINST CTLA-4
Pembrolizumab Atezolizumab Ipilimumab
Nivolumab Durvalumab
Avelumab
114

DRUG DOSAGE DURATION
Pembrolizumab 200mg IV q3Wk Until disease progression or
unacceptable toxicity
Nivolumab 240mg IV q2wk or
480mg IV q4wk
Until disease progression or
unacceptable toxicity
Nivolumab + Ipilimumab 3mg/kg IV Nivolumab
immediately followed by
ipilimumab (1mg/kg IV) on
the same day every 3 weeks
Upto 4 doses or unacceptable
toxicity
115

 Severe autoimmunity
 Hypophysitis
 Vitiligo
 Diarrhoea
116

 Tyrosine kinase inhibitors
 VEGF inhibitors
 mTOR inhibitors
Sorafenib
Sunitinib
Pazopanib
Axitinib
Cabozantinib
Lenvatinib
Tivozanib
Bevacizumab
Everolimus
Temsirolimus
117

118

 Oral TKI
 Activity against – VEGFR,PDGFR,raf-1
 Dose – 400mg BD x 12 weeks
 Side effects – Hypertension, fatigue, rash, hand foot syndrome, diarrhoea
 Currently infrequently used in first line setting
 Patients whose disease has progressed on other VEGFR inhibitors may
respond favourably
119

 Oral TKI
 Inhibits – VEGFR, PDGFR, cKit, fms like tyrosine kinase 3
 Widely used in initial management of ccRCC
 Started after 14 days following CN
 Dose: 50 mg OD for 4 weeks followed by 2 weeks off (as long as
tolerable)
120

 SE: diarrhoea,rash,hand foot syndrome, fatigue,asthenia,
hypertension
 Bone marrow suppression & hypothyroidism – notable side effects
121

 Selective activity against VEGFR
 Also inhibits PDGFR & FGFR
 800mg OD
 Decreased side effects
 Reasonable first line option
 Better tolerated
 Increased incidence of hepatotoxicity
122

 Highly selective oral TKI of VEGFR (1,2,3)
 Dose: 5mg BD
 MC side effects: diarrhoea,fatigue,hypertension
123

 Cabozantinib - Oral inhibitor of TK, MET,VEGR, AXL
 Lenvatinib – Oral inhibitor of VEGFR(1,2,3), FGFR(1,2,3), PDGFR, RET,
c-KIT
 Nintedanib – VEGFR1,2,3, PDGFR, FGFR1,2,3,RET, Flt-3
 Dovitinib – VEGFR, PDGFR, FGFR
 Tivozanib – Highly selective inhibitor ofVEGFR1,2,3
124

 Monoclonal antibody against VEGF
 Dose: 10mg /kg iv every 2 weeks
 4 weeks after CN
 SE: bleeding, hypertension,fatigue, proteinuria
 For improving efficacy – combined with IFNalpha
 Not used as single agent in initial therapy
 Role in patients who failed initial first line agents
125

 25mg IV once weekly
 Not recommended in VEGF TKI refractory
disease
 Used in
 Poor risk disease
 Non clear cell RCC
126

 Oral agent – 10mg OD
 Established in treatment of
VEGF refractory disease
 Used in High risk disease
 Non clear cell RCC
127

 Rashes
 Mucositis
 Hepatic dysfunction
 Hyper-cholestrolemia
 Hyper-glycemia
 Hypophosphatemia
 Stomatitis
 Gastritis
128

 Conventional cytotoxic chemotherapy has been largely ineffective in the
management of clear cell RCC
 Overall response rate is 5.5% to 6.0%
 Response in Collecting duct carcinoma
 Sarcomatoid component
 A small case series has suggested promising activity for gemcitabine-
based chemotherapy
129

EAU 2019
130

EAU 2020
131

EAU 2020
132

 Do not offer chemotherapy to patients with metastatic renal cell carcinoma.
 The combination of pembrolizumab and axitinib in treatment-naive
patients with cc-mRCC across all IMDC risk groups demonstrated OS
and ORR benefits compared to sunitinib.
 The combination of nivolumab and ipilimumab in treatment-naive
patients with clear-cell-mRCC(cc-mRCC) of IMDC intermediate and poor
risk demonstrated OS and ORR benefits compared to sunitinib
133

 Currently,PD-L1 expression is not used for patient selection.
 Axitinib can be continued if immune-related adverse events results in
cessation of axitinib and pembrolizumab
 Patients who do not receive the full 4 doses of ipilimumab due to
toxicity should continue on single agent nivolumab,where safe and
feasible
134

 Do not re-challenge patients who stopped immune checkpoint inhibitors because
of toxicity without expert guidance and support from a multidisciplinary team.
 Offer nivolumab after one or two lines of vascular endothelial growth factor-
targeted therapy in mRCC.
 Offer sunitinib or pazopanib to treatment-naive patients with IMDC favourable,
intermediate,and poor-risk cc-mRCC who cannot receive or tolerate immune
checkpoint inhibition.
 Offer cabozantinib to treatment-naive patients with IMDC intermediate- and poor-
risk cc-mRCC who cannot receive or tolerate immune checkpoint inhibition.
135

 Single-agent cabozantinib or nivolumab are superior to everolimus
after one or more lines of VEGFtargeted therapy
 Everolimus is no longer widely recommended before third-line
therapy.
136

 Sunitinib
 mTOR inhibitors
 VEGFR inhibitors – modest efficacy in papillary RCC
 Foretinib – TKI against MET & VEGFR2 – HPRCC
 Bevacizumab + Erlotinib – FH mutations (Type II Papillary RCC)
Both mTOR inhibitors and VEGF-targeted therapies have limited activity in non-cc-mRCC.
There is a non-significant trend for improved oncological outcomes for sunitinib over everolimus.
137

138

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