2. Anatomy of Kidney
pair of organs located in the abdominal
cavity on either side of the spine in a
retroperitoneal position.
Adrenal glands rest on top of each kidney
Approx. at vertebral level T12 to L3, right
kidney being slightly lower than the left.
Long axis of kidney is directed downward
and laterally
Approx. 11–14 cm in length, 6 cm wide and
4 cm thick
weighs around 150 gm in males & 135 gm in
females.
Mobile Organ, move vertically within
retroperitoneum 0.9 cm to 1.3 cm., as much
as 4 cm during normal respiration
2
3. The kidney is surrounded by tough fibrous
tissue, the renal capsule, which is itself
surrounded by perinephric fat, renal fascia
(of Gerota) and paranephric fat.
parenchyma, of the kidney is divided into
two major structures: renal cortex and
renal medulla
Fig: Anterior relations of kidneys Fig: Posterior relations of kidneys 3
4. Blood Supply
Approx. 20% of the cardiac output .
From renal arteries, left and right, which branch directly from the abdominal aorta.
renal vein emerges from hilum and drains into the inferior vena cava.
Lymph Drainage : to the lateral aortic lymph nodes around the origin of the renal
artery.
Nerve Supply:
Through renal sympathetic plexus (T10 – L1) fibres, mainly vasomotor.
Afferent nerves T10 to T12 thoracic nerves.
Functions
Excretion of wastes,
Acid-base homeostasis,
Osmolality regulation, Blood pressure regulation and Hormone secretion
4
5. Renal Tumors
51,000 cases diagnosed and
more than 12,900 deaths
annually in the US
Account for approx. 3% of
adult malignancy
5
7. Renal Cell Carcinoma
First described by Konig in 1826.
In 1883 Grawitz, noted the fatty content of cancer cells
similar to that of adrenal cells.
All these tumors arise from Renal tubular epithelium.
accounts for 80–85% of kidney cancer
2% to 4% increase in incidence per year
7
8. Epidemiology
Male predominance (1.6:1.0 M:F)
Highest incidence between age 50-70
-Median age of diagnosis is 66 years
-Median age of death 70 years
Majority of RCC occurs sporadically
Highest incidence in Scandinavia and North America,
lowest in Africa
8
9. Risk Factors
Tobacco smoking contributes to 24-30% of RCC cases
- Tobacco results in a 2-fold increased risk
Environmental:
Cadmium, thorium-di-oxide, petroleum and phenacetin analgesics.
Occupational:
leather tanners, shoe workers, asbestos workers.
Hormonal:
diethylistillbestrol,
Obesity, HTN
35% - 47% pt on long term dialysis develop Acquired
polycystic kidney disease, out of which 5.8% develops
Renal cancer.
9
10. RCC is not one disease…
It is made up of no. of different types of cancers with different histology, different
clinical courses and caused by different gene.
Type Clear cell Papillary type 1 Papillary type 2 Chromophobe Oncocytoma
Incidence (%) 75% 5% 10% 5% 5%
Associated VHL c-Met FH BHD BHD
mutations
A sarcomatoid variant represents1% to 6% of renal cell carcinoma and these tumors are
associated with a significantly poorer prognosis.
BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.
10
11. Hereditary Renal Cancer Syndromes
Syndrome Chromosome Renal Other Manifestations
Location Manifestations
(Gene)
Von Hippel- 3p25 Clear cell renal Retinal and central nervous system
Lindau (VHL) VHL carcinoma: solid hemangioblastomas; pheochromocytomas;
and/or cystic, pancreatic cysts and neuroendocrine
multiple and tumors; endolymphatic sac tumors;
bilateral epididymal and broad ligament
28%-45% cystadenomas
11
12. Syndrome Chromosome Renal Manifestations Other Manifestations
Location (Gene)
Hereditary papillary 7q31 Papillary renal carcinoma None
renal carcinoma MET type 1: solid, multiple and
type1(HPRC) bilateral
Hereditary 1q42-43 Papillary renal carcinoma Uterine leiomyomas
leiomyomatosis and FH type 2, collecting duct and leiomyosarcomas;
renal cell carcinoma carcinoma: solitary, cutaneous leiomyomas
(HLRCC) aggressive
12
15. Natural History
7% diagnosed incidentally
45% present with localized disease, 25% with
locally advanced disease, 30% with metastatic
disease
Lymph node metastases- 9% to 27% (renal hilar,
para-aortic and paracaval)
Renal vein – 21% & IVC 4%
Distant metastases- lung (75%), soft tissue (36%),
bone (20%), liver (18%), skin (8%) and CNS (8%)
15
16. Clinical Presentation
Clinically occult for most of its course.
Classic triad (occur in 5%-10% of patients)
flank pain,
hematuria,
palpable abdominal mass
Hematuria present 40% of patients
Systemic symptoms
Anaemia, Fatigue, Cachexia, Wt. Loss, Hypercalcemia,
Hepatic Dysfunction
Paraneoplastic Syndrome
Parathyroid like hormones, erythropoietin, renin,
gonadotropins, placental lactogen, prolactin, enteroglucagon,
insulin like hormones, adrenocorticotropic hormone and
prostaglandins identified in RCC pt.
16
17. Diagnostic Work-Up
General-History, Physical examination
Laboratory studies
CBC, LFT's, alkaline phosphotase, BUN, creatinine, urinalysis
Radiographic studies- Increased use of imaging has increased the
detection of renal lesions most of which are simple cysts.
X-Ray KUB region
Ultrasonography- Excellent in distinguishing cystic from solid masses
Intravenous Urography - Starting point for hematuria evaluations and
function of contralateral kidney
Computed tomography- Provides an excellent assessment of the
parenchyma and nodal status.
Magnetic Resonance Imaging - excellent demonstration of solid renal
masses and is image test of choice to demonstrate extent of vena caval
involvement with tumor. Useful in patients with renal insufficiency
17
18. Metastatic Work-Up
Chest X-ray or Chest CT
CT/MRI scan of abdomen or pelvis
Bone scan with plan films (for elevated alkaline
phosphatase or bone pain).
18
19. Figure : Computed tomography demonstrates
a right renal carcinoma (m) with a large
contralateral adrenal metastasis (a).
Figure: CT scan shows large left renal mass
with calcification (m) invading the left renal
vein (arrow).
19
20. Figure: T1-weighted magnetic
resonance image demonstrates
tumor (m) and vascular invasion
(arrow). Flowing blood (v) in the
left renal vein is black on this scan.
Figure A: Axial T1-weighted
image demonstrates a large left
renal carcinoma with extension
into the left renal vein (m) with
protrusion into the IVC (v). B:
Sagittal T1-weighted image
shows the relation of the tumor
thrombus (m) to the IVC (v) in
the lateral projection.
20
21. Robson Modification Of the Flocks &
Kadesky Staging of RCC
Tumor Stage Description
I Renal cell carcinoma is confined to the kidneys
II Renal cell carcinoma extends through the renal capsule but is
confined to Gerota’s fascia
III Renal cell carcinoma involves the renal vein or inferior vena cava
(IIIA) or the renal hilar lymph nodes (IIIB)
IV Renal cell carcinoma has spread to local adjacent organs (other
than adrenal gland) or to distant sites
21
22. TNM staging
T - primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour confined to kidney, <7cm
T1a ≤4cm, confined to kidney
T1b >4cm but <7cm, confined to kidney
T2 Tumour >7cm, confined to kidney
T3 Tumour extends into major veins or adrenal or perinephric tissue but not beyond Gerota’s fascia
T3a Direct invasion of adrenal gland, perirenal and/or sinus fat
T3b Gross extension into renal vein or IVC
T3c Extends into IVC above diaphragm or wall of IVC
T4 Invasion beyond Gerota’s fascia
N - regional lymph nodes
NX Nodes cannot be assessed
N0 Regional lymph nodes not involved
N1 Metastasis in a single regional lymph node
N2 Metastases in >1 regional lymph node
M - distant metastases
MX Metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases
22
23. Staging I T1 N0 M0
II T2 N0 M0
T3 N0 M0
- Stage I-III: Localized disease
III T1 N1 M0
- Stage IV: Advanced, metastatic T2 N1 M0
disease T4 N0 M0
T4 N1 M0
IV
Any T N2 M0
Any T Any N M1
23
24. Prognostic factors for RCC
Pathologic stage 5 yr survival
T1 - 2 organ confined 70-90%
T3 50-70%
N+, M1 5-30%
Tumour size
< 4 cm > 90%
4 - 10 cm 50%
> 10 cm 0%
Histological type
Clear cell 70%
Papillary, Chromophobe 85%
Multilocular cystic 100%
Medullary, Collecting duct 0%
24
27. Surgery- Radical nephrectomy
Gold standard treatment for localized RCC with
contralateral normal kidney, adequate surgical
margin.
Principles of Surgery- Early ligation of renal artery
and vein , removal of kidney including Gerota’s
fascia, removal of ipsilateral adrenal gland, regional
lymphadenectomy from crus of diaphragm to aortic
bifurcation.
27
28. Nephron Sparing Surgery
Indications
1. Bilateral RCC
2. RCC in a solitary functioning kidney
3. Unilateral RCC with contralateral kidney under threat of its future function
(Renal artery stenosis, Chronic pyelonephritis , Hydronephrosis, Ureteral
reflux, Calculus disease, Systemic disease such as diabetes )
4. Tumor less than 4cms with normal opposite kidney.
5. Five year survival rate 75% to 85%
6. Local tumor recurrence of 10% is reported.
Other Approaches
1. Radio frequency ablations
2. Cryo ablation
28
29. Radiotherapy
Radiosensitivity of RCC is variable
Animal experiments suggest a theoretical benefit
to preoperative RT (? Reduce intra-operative
seeding)
Historically several series suggested clinical
benefit to adjuvant (post-op) RT
Limited applicability because of long time span,
improvements in staging, surgery, changing RT
technology
29
30. Neo-adjuvant radiotherapy
Rotterdam study
Radical nephrectomy vs neo-adjuvant RT (30Gy/15#
APPA) plus nephrectomy
No overall survival or metastasis-free survival advantage
(both 50% 5-year survival)
No improvement in resectability
Further study to 40Gy - still no advantage
Swedish study
Poorer 5-year survival with pre-op RT (47% vs 63%)!
30
31. Adjuvant radiotherapy
Some early studies suggested advantage to post-op
RT but poorly designed and reported
Newcastle (UK) study
Poorer survival with adjuvant RT (55Gy) vs surgery alone
Not stratified by grade or stage
Copenhagen study
Stage II/III disease
No difference in RCC relapse
Significantly more GI complications (44%) in RT group
19% of deaths attributed to RT complications
31
32. Role of RT
MSKCC and Kao retrospective series
Potential benefit of RT in selected cases where there is a
high risk of local failure, ie:
Pre-op RT in unresectable, locally-advanced tumours
(“downstaging”), including T3a/T3c
T3b (vena cava invasion) doesn’t necessarily increase risk of local
failure
Incomplete resection with positive margins
Lymph node involvement
RT in these cases may improve local control but
probably not overall survival
Clear role in palliation
32
33. RT Techniques
High energy photons (10 mv or above) from linear
accelerator
Conventional External Beam Radiation.
Technique-
AP/ PA field
AP/PA + Oblique field (in large tumor)
Portal
Upper- T10 – T11 Vertebra
Lower- transverse process of L3
Medial- 2 cm from midline or covering the opposite renal pelvis
Lateral- whole flank or tumor
For Rt. Sided tumor field reduction after dose of 3600cGy to
4ooocGy
Safe dose: 5040 cGy in 180 cGy/# over a period of 5-6 weeks
Boost of 540 cGy in 3# to small volume
Total dose: 5580 cGy
33
34. RT techniques
Pre-op RT 40-50Gy to kidney + lymphatics for
unresectable lesions may improve resectability
45-50Gy post-op in 1.8 to 2 Gy daily fraction
nephrectomy bed and lymph node drainage site
10-15Gy boost (ie. ~60Gy total) to gross residual disease
Include scar to reduce chance of scar recurrence
Dose limitations (fully fractionated)
Liver D30 <36-40Gy
Contralateral kidney <20Gy max
Spinal cord <45Gy max
34
35. Three-dimensional (3D) conformal radiation
therapy
CT planned, to image and reconstruct the tumor &
surrounding kidney tissue in 3D
Multiple field techniques, radiation beams can be
shaped exactly to the contour of the treatment
area, nearby normal tissue is usually spared.
35
36. Figure: A CT-based treatment plan using a combination of four fields (anterior, posterior, right
lateral, and right posterior oblique) to cover the tumor bed (dark oval) with 54 Gy (isodose line
displayed). This combination of fields and beam’s-eye-view shaping allows sparing of the liver,
bowel, and spinal cord
36
37. Intensity Modulated Radiation Therapy
(IMRT)
State-of-the-art radiation system.
Treat difficult-to-reach tumors.
Effectively treat tumor that surrounds spinal cord with very
little radiation reaching cord.
Reasonable consideration in kidney cancer due to
sensitivity of adjacent surrounding structures.
Useful if previously had conventional radiation therapy for
kidney cancer, and are experiencing recurrent tumors in
the treated area.
37
38. Management of Metastatic Disease
Metastatic
Disease
Radio Chemo Targeted Immuno
Surgery
Therapy Therapy Therapy Therapy
38
39. Surgery
Palliative Nephrectomy – Indicated in patients with
Severe hemorrhage,
Severe pain,
Paraneoplastic syndrome
or compression of adjacent viscera
Solitary metastasis can be resected and may show some survival
advantage
Therapeutic:
Not curative but produce some long-term survivors.
The possibility of disease-free survival increases after resection of
primary tumor and isolated metastasis excision.
to decrease tumor burden in preparation for subsequent therapy
39
40. Surgery…
Resection of met’s
in pt. not relieved from palliative RT
In solitary mets.
Spontaneous regression of met’s
< 1 % of cases
only 4 (0.8%) of 474 patients in 9 series who underwent
nephrectomy experienced regression of metastatic foci
40
41. Radio Therapy
Palliation
Used for local or symptomatic metastatic disease, such
as painful osseous lesions or brain metastasis.
Treatment field encompasses metastatic deposit (or
local recurrence) with 2-3cm margins
Higher doses (up to 35-40Gy) may be required to
overcome radioresistance
Symptomatic relief in 64-84% of patients
41
42. Chemotherapy
RCC is a chemo resistant tumor. Phenomenon due to
presence of multi drug resistant glycoprotein (MDR)
in tumor cell - causes extrusion of the drug
Conventional therapy has little to offer
5-FU alone has a response rate of 10%,
On-going clinical trials of combination chemotherapy
including Gemcitabine and 5-FU
Limited data reveals some response in non-clear cell
RCC to Carboplatin, Cisplatin plus Gemcitabine
42
43. Targeted Molecular Therapy
New treatment approach that targets only the cancer.
In renal cell carcinoma patients, this type of therapy
uses drugs that stop the new blood vessels from
growing, and targets certain factors that cause the cells
to grow.
Tyrosine kinase (TK) inhibitors block the
intracellular domain of the VGEF receptor
- Sunitinib (Sutent)
- Sorafenib (Nexavar)
43
44. Targeted Molecular Therapy…
Monoclonal antibody that binds circulating VEGF
preventing the activation of the VEGF receptor
- Bevacizumab (Avastin)
Mammalian target of rapamycin (mTor) inhibitors
Temsirolimus (TMSR)
44
45. Immunotherapy
Systemic type of treatment used to improve the body’s
natural defenses.
Boosts the immune system and slows down the cancer
growth
Clinical response to immunotherapy seen in patients with
1. Good performance status
2. Had a prior nephrectomy
3. Non bulky pulmonary or soft tissue metastasis
4. Asymptomatic patient
Interferon (IFN)
Interleukin (IL -2)
45
46. Summary
RCC is relatively rare but increasing incidence
Associated with tobacco and inherited disorders
Surgery is the only curative modality for Stage I, II, and
III
RCC is radio resistant, RT’s role in paliation
Stage IV disease holds poor prognosis despite
advancements in molecular understanding
IL-2, Sorafenib, Sunitinib, and Temsirolimus are FDA
approved treatments for advanced RCC
46