CLINICAL FEATURES & PROGNOSTIC FACTORS OF RCC

Renal cell carcinoma
CLINICAL FEATURES & PROGNOSTIC
FACTORS
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

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

CLINICAL
FEATURES
• INCIDENTAL
• SYMPTOMS OF LOCALISED DISEASE
• SYMPTOMS OF SYSTEMIC DISEASE
3
Dept of Urology, GRH and KMC, Chennai.

INCIDENTAL
PRESENTATION
Sequestered location within
retroperitoneum
Asymptomatic and non
palpable until locally advanced
More than 60% - incidental
4

Localised
Disease
“TOO LATE TRIAD”
• Flank pain
• Abdominal mass
• Hematuria
Spontaneous Perirenal hematoma
• More than 50% of patients with perirenal
hematoma of unclear etiology have an
occult renal tumor
• Most common – AML or RCC
5

Advanced
disease
Constitutional
symptoms
• Weight loss
• Fever
• Malaise
Obstruction
of IVC
• Bilateral lower extremity edema
• Non reducing varicocele
Metastatic
disease
• Persistent cough
• Bone pain
• Cervical lymphadenopathy
6

PARANEOPLASTIC
SYNDROMES
10 – 20%
1,25-dihydroxycholecalciferol, renin, erythropoietin, and
various prostaglandins - pathologic amounts
Elaborate a variety of other physiologically important factors
• Parathyroid hormone–like peptides
• Lupus-type anticoagulant
• Human chorionic gonadotropin
• Insulin
• Various cytokines and inflammatory mediators
Responsible for the development of constitutional symptoms
such as weight loss, anemia, and paraneoplastic syndromes
7

INCIDENCE
OF SYSTEMIC
SYNDROMES
8

HYPERCALCEMIA
Reported in upto 13%
Due to either paraneoplastic syndrome or
osteolytic metastasis
Most common paraneoplastic etiology –
parathyroid hormone like peptide
Others – Tumor derived 1,25
dihydroxycholecalciferol, Prostaglandins
C/F - Nonspecific and include nausea, anorexia,
fatigue, and decreased deep tendon reflexes
9

HYPERTENSION
Increased production of renin
Compression or encasement of renal artery or its
branches
Arteriovenous fistula within the tumor
Polycythemia
Hypercalcemia
Ureteral obstruction
Increased intracranial pressure with cerebral
metastasis
10

POLYCYTHEMIA
Increased erythropoietin
production
From the tumor
Adjacent parenchyma in response
to hypoxia induced by tumor
growth
11

STAUFFER SYNDROME
Nonmetastatic hepatic dysfunction
3% to 20%
Findings
• Elevated serum alkaline phosphatase level – in almost all
• 67% - elevated prothrombin time or hypoalbuminemia
• 20% to 30% - elevated serum bilirubin or transaminase levels
• Other - thrombocytopenia and neutropenia, fever, weight loss - discrete regions
of hepatic necrosis.
12

STAUFFER
SYNDROME
Hepatic metastases must be excluded.
Biopsy - nonspecific hepatitis associated with a prominent
lymphocytic infiltrate.
Elevated serum levels of IL-6 and other cytokines may play a
pathogenic role.
Hepatic function normalizes after nephrectomy in 60% to
70% of cases.
Persistence or recurrence of hepatic dysfunction is almost
always indicative of the presence of viable tumor and thus
represents a poor prognostic finding
13

OTHER
PARANEOPLASTIC
SYNDROMES
• Cushing syndrome
• Hyperglycemia
• Galactorrhea
• Neuromyopathy
• Clotting disorders
• Cerebellar ataxia
In general, treatment of paraneoplastic
syndromes associated with RCC has required
surgical excision or systemic therapy and, except
for hypercalcemia, medical therapies have not
proved helpful
14

INVESTIGATIONS
15

INITIAL
LABORATORY
INVESTIGATIONS
Urinalysis (UA) with urine cytology (if central lesion)
Urine cytology (if central lesion is present, to evaluate for
urothelial carcinoma)
Complete blood cell (CBC) count with differential
Electrolytes
Renal profile
Liver function tests (LFTs): Aspartate aminotransferase (AST)
and alanine aminotransferase (ALT)
Serum calcium
Other tests as indicated by the patient’s presenting symptoms.
16

17

18

CT KUB
A dedicated renal CT examination consists of thin-
section (2.5-5 mm) helical imaging of the kidneys
before the intravenous administration of contrast
agent, followed by imaging 60-70 seconds and 3-5
minutes after administration of the contrast agent.
The imaging parameters (kilovoltage,
microamperage, field of view, section thickness)
should be kept constant for all phases of imaging to
enable comparison of the attenuation
measurements.
The addition of an arterial phase CT (either with
bolus tracking or after a 20-25 second delay) with
thin slices (1-2 mm)
19

CT SCAN
•Non-contrast CT the lesions are
soft tissue attenuation between
20-70 HU
•Larger lesions - frequently have
areas of necrosis
•Approximately 30%
demonstrate some calcification
20

NON-
CONTRAST CT
– TUMOR
NECROSIS
21

TUMOR
CALCIFICATION
22

CECT KUB –
CORTICOMED
ULLARY PHASE
• 25-70 seconds after administration of
contrast
• Renal cell carcinomas - variable
enhancement, usually less than the
normal cortex.
• Small lesions may enhance a similar
amount and be difficult to detect
• Small lesions enhance homogeneously,
whereas larger lesions have irregular
enhancement due to areas of necrosis
• Clear cell subtype may show much
stronger enhancement
• Also best for assessing vascular anatomy
23

CECT KUB
• The nephrogenic phase (80-180
seconds) is the most sensitive
phase for detection of abnormal
contrast enhancement.
• Enhancement more than 15 HU –
RCC until proved otherwise
• Excretory phase - In assessing the
collecting system anatomy
especially if the candidate is a
potential candidate for a partial
nephrectomy.
24

CECT - RCC
25

CECT - RCC
33.9 HU 75.8 HU
26

CYSTIC RCC
25.8 HU
47.1 HU
27

MRI
• Infrequently used
• Indications :
• ALLERGY
• RENAL COMPROMISE
• PREGNANCY
• CONCERN FOR RADIATION
EXPOSURE
• EQUIVOCAL CT FINDINGS
28

MRI
• Excellent at imaging the kidneys and
locally staging tumours
• Suggest the likely histology, on the
grounds of T2 differences.
• T1: often heterogeneous due to necrosis,
haemorrhage and solid components
• T2: appearances depend on histology
• clear cell RCC: hyperintense
• papillary RCC: hypointense
• T1 C+ (Gd): often shows prompt arterial
enhancement
29

MRI
• Tumor pseudo capsule - hypointense rim
between the tumour and the adjacent
normal renal parenchyma
• For imaging renal vein and IVC tumour
thrombus – preoperative planning
• Enhancement in the thrombus
• Diffusion-weighted sequences -
indeterminate small renal lesions
• Inflammatory or malignant in nature
• Both exhibit restricted diffusion
• Restriction is greater with abscess than
tumour
30

MRI
31

T2W CORONAL
RIGHT RCC WITH RENAL VEIN & IVC
THROMBUS
32

T1W BEFORE & AFTER CONTRAST
33

T2W AXIAL
34

Renal Angiography
• Limited role
• Establishment of
neovascularity in
equivocal cases – RCC
• Primarily reserved for
concomitant renal
artery disease
35

Positron Emission
Tomography
• Not routinely used
• Indications :
• High risk for RCC but with
equivocal findings on
conventional imaging
• Metastatic RCC
• Good specificity, but low
sensitivity
• Immunoscintigraphy with
radiolabelled monoclonal Ab to
CA-9 – investigational stage
36

Tissue
diagnosis
• Traditionally been of limited value
• Indications :
• Suspected renal abscess or
infected cyst
• Renal lymphoma
• Metastatic malignant RCC

RENAL MASS
BIOPSY –
TISSUE
DIAGNOSIS
Indications :
1. Metastatic RCC
2. Unresectable
primary tumors
3. Indeterminate
recurrences
4. Cancers metastatic
to kidney
5. Precious kidney
with doubtful
diagnosis
Complications:
➢Bleeding (5-
7%)
➢Infection
➢Arteriovenous
fistula
➢Needle track
seedling
(0.01%)
➢Pneumothorax
➢Usually, morbidity
rate is 5%
38

Immunohistochemistry
•Just in the evolution stage
•FNAB combined with CA-9 –
improved sensitivity
•Positive immuno reactivity for
HMB-45, a melanoma
associated antigen –
characteristic of AML
•To differentiate AML from
sarcoma of kidney

GUIDELINES FOR
DIAGNOSIS
40

AUA
GUIDELINES
2017
• For the management of clinically localized
sporadic renal masses suspicious - high-
quality, multiphase, cross-sectional
abdominal imaging to optimally
characterize and clinically stage the renal
mass
• Characterization of the renal mass should
include assessment of the following:
• Tumor complexity
• Degree of contrast enhancement (where
applicable)
• Presence or absence of fat
41

AUA
GUIDELINES
2017
• Biopsy should be considered when a mass is
suspected to be hematologic, metastatic,
inflammatory, or infectious
• In the setting of a solid renal mass, biopsy is
not required for either of the following:
• Young or healthy patients who are unwilling
to accept the uncertainties associated with
biopsy
• Older or frail patients who will be managed
conservatively independent of biopsy
findings
• For patients with a solid renal mass who elect
biopsy, multiple core biopsies are preferred
over fine needle aspiration
42

EAU
GUIDELINES
2018
• Multi-phasic contrast-enhanced computed
tomography (CT) of abdomen and chest for
the diagnosis and staging of renal tumours.
• MRI to better evaluate venous involvement,
reduce radiation or avoid intravenous CT
contrast medium.
• Non-ionising modalities, mainly contrast
enhanced ultrasound (CEUS), for further
characterisation of small renal masses,
tumour thrombus and differentiation of
unclear renal masses.
• NO ROUTINE bone scan and/or positron-
emission tomography (PET) CT for staging of
RCC.
43

EAU
GUIDELINE
2018
• Renal tumour biopsy before ablative
therapy and systemic therapy without
previous pathology.
• Percutaneous biopsy in select patients
who are considered for active
surveillance;
• Coaxial CORE BIOPSY technique when
performing a renal tumour biopsy
• Do not perform a renal tumour biopsy
of cystic renal masses
44

NCCN
GUIDELINES
• History and physical examination
• Complete blood count, comprehensive
metabolic panel, and urinalysis
• Abdominal/pelvic CT or abdominal MRI,
with contrast when clinically indicated
• Chest x-ray
• Bone scan, brain MRI, chest CT, if clinically
indicated
• Recommends considering needle biopsy of
small lesions if clinically indicated
• Recommends considering urine cytology
and ureteroscopy if urothelial carcinoma is
suspected (eg, a central mass is present).
45

ESMO 2016
• Diagnosis is usually suggested by ultrasound
and further investigated by CT scan.
• Magnetic resonance imaging (MRI) may
provide additional information in investigating
local advancement and venous involvement by
tumour thrombus.
• Contrast-enhanced chest, abdominal, and
pelvic CT is mandatory for staging; In case of
an allergy to CT contrast medium, a high-
resolution CT scan of the chest without
contrast medium, together with an abdominal
MRI may be used.
• Unless clinically indicated, the use of bone
scan or CT (or MRI) of the brain is not
recommended for routine clinical practice
46

ESMO 2016
• Positron emission tomography is not a
standard investigation in the diagnosis
and staging of RCC
• A diagnostic biopsy is required before
treatment with ablative therapies; it is
also indicated in patients with metastatic
disease before initiating systemic
treatment.
• The final histopathologic diagnosis,
classification, grading, and evaluation of
prognostic factors should be based on
the nephrectomy specimen when
available
47

ROLE OF
SCREENING
48

PROGNOSTIC
FACTORS
• CLINICAL FACTORS
• ANATOMICAL FACTORS
• HISTOLOGICAL FACTORS
• MOLECULAR FACTORS
49

CLINICAL
Symptomatic presentation
Weight loss of more than 10%
of body weight
Poor performance status
Paraneoplastic signs or
symptoms
50

ANATOMICAL FACTORS
TNM
STAGING
TUMOR
SIZE
51

PATHOLOGICAL STAGE
• Single most important prognostic factor
• Extent of locoregional or systemic disease at
diagnosis is the primary determinant of outcome
for this disease
• Higher T stage, lymph node and distant metastasis
– worse prognosis; shorter survival
52

53

54

PERIRENAL / RENAL SINUS FAT INVASION
Renal sinus fat involvement
along with perinephric fat
invasion (T3a) - higher risk
for metastasis related to
increased access to the
venous system
Collecting system invasion -
poorer prognosis in
otherwise organ-confined
RCC
55

VENOUS
INVOLVEMENT
• Even microscopic venous or lymphatic
involvement - poor prognostic sign
• Involvement of IVC whether above or below
diaphragm – not prognostically different; better
prognosis when compared with perinephric fat
or nodal involvement
• Direct invasion of the wall of the vein appears
to be a more important prognostic factor than
level of tumor thrombus and is now classified as
pT3c independent of the level of tumor
thrombus
56

ADRENAL
INVOLVEMENT
• 1 – 2%
• Most patients with direct or metastatic
ipsilateral adrenal involvement eventually
succumb to systemic disease progression
• Involvement of ipsilateral adrenal gland –
outcomes equivalent to stage IV disease
• Suggesting - hematogenous route of
dissemination or a highly invasive phenotype
57

STAGE T4
• Poor prognosis with extension beyond the
Gerota fascia to involve contiguous organs
(stage T4) and in patients with lymph node or
systemic metastases
• Synchronous metastases
• Worse outcome
• Many patients dying of disease progression
within 1 to 2 years
• Asynchronous metastases
• Metastasis-free interval - prognosticator
• Reflects the tempo of disease
progression
58

PROGNOSTIC FACTORS IN METASTASES
• Performance status
• Number and sites of metastases
• Anemia, hypercalcemia, elevated alkaline phosphatase or lactate
dehydrogenase levels, thrombocytosis
• Sarcomatoid histology
• Presence of bone, brain, and/or liver metastases and multiple
metastatic sites
59

TUMOR SIZE
• Independent prognostic factor for both organ-confined and
invasive RCC
• Larger tumors are more likely to exhibit clear cell histology and
high nuclear grade
• Both of these factors correlate with a compromised prognosis
60

HISTOLOGICAL FEATURES
FUHRMAN NUCLEAR GRADE
HISTOLOGIC SUBTYPE
PRESENCE OF SARCOMATOID COMPONENT
MICROVASCULAR INVASION
TUMOR NECROSIS
COLLECTING SYSTEM INVASION
61

FUHRMAN’S NUCLEAR GRADE
More effective than other parameters in predicting distant metastasis following nephrectomy
NUCLEAR GRADE 5 YEAR SURVIVAL
1 64%
2 34%
3 31%
4 10%
Prognostic significance in clear cell and papillary RCC
Other histological subtypes – not entirely clear 62

HISTOLOGIC
SUBTYPE
• Clear cell – most aggressive
• Followed by – papillary and chromophobe
• RCC with sarcomatoid features
• Renal medullary or unclassified histology
• Papillary tumors
• Type I – low grade, multifocal, favourable
outcome
• Type II – high grade, increased metastatic
potential
63

64

MOLECULAR
FACTORS
Ki67
• Increased proliferative index
• Reduced survival in clear cell RCC
CARBONIC ANHYDRASE IX
• REGULATED BY VHL GENE
• Decreased expression associated with poor survival in metastatic RCC
• Marker for response to systemic therapy
B7-H1
• T cell coregulatory molecule
• Strong independent predictor of disease progression
Other Factors
• Cell cycle regulators like TP53
• Growth factors and their receptors – VEGF
• Adhesion molecules
• Survivin
• Down regulation of genes involved in TCA cycle and upregulation of
pentose phosphate pathway 65

66

SCORING
SYSTEMS
• Preoperative Aspects and Dimensions
Used for an Anatomical (PADUA)
classification system
• R.E.N.A.L. nephrometry score
• C-index
• Arterial Based Complexity (ABC)
Scoring System
• Zonal NePhRO scoring system
67

R.E.N.A.L
SCORING
SYSTEM
68

PADUA
SCORING
SYSTEM
69

C INDEX
• Ratio of the distance (c) between the tumor center
and the kidney center, and the tumor radius (r)
• Measure tumor centrality
• C index of less than 1 has some portion of the
tumor superimposed on the kidney center
• C index of 1 equates to a tumor with its edge lying
on the center
• As the centrality index increases, the tumor
periphery becomes more distant from the kidney
center (less complexity).
70

ABC SCORING
SYSTEM
• Category 1 - Tumors of renal cortex -
interlobular and arcuate arteries
• Category 2 - included tumors
originating from or extending to the
renal - interlobar arteries
• Category 3S - Extending into the renal
sinus towards the central collecting
system - segmental arteries and their
branches
• Category 3H - Tumors in proximity of or
involving the renal hilar vessels
71

72

RISK STRATIFICATION SYSTEM
UCLA INTEGRATED
STAGING SYSTEM
(UISS)
MAYO CLINIC
STAGE, SIZE, GRADE
AND NECROSIS
(SSIGN) SCORE
MSKCC STAGING
SYSTEM
73

SSIGN
• Mayo clinic
• Assess cancer specific survival in patients with
clear cell RCC who underwent radical
nephrectomy
• Factors included
• TNM stage, tumor size, nuclear grade and
tumor necrosis
• Predictive accuracy – 81-88%
74

UISS
UCLA integrated staging system
Developed using kidney cancer databes from University
of California Los Angeles Kidney Cancer Program
Goal – Predicting survival
Factors – Tumor stage, Fuhrman nuclear grade, ECOG
performance status
Used to stratify both localized and metastatic RCC into
three different risk groups
Predictive accuracy – 86%
75

MSKCC
STAGING
SYSTEM
Histology
Tumor size
T stage
Symptoms at presentation
Aim – predict probability of RCC recurrence
after nephrectomy
76

Leibovich
Nomogram
Developed by Leibovich et.al (2003)
Algorithm to predict progression to
metastases after radical nephrectomy
in clinically localized clear cell RCC
Tumor stage, size, grade, necrosis and
regional lymph node status
77

Karakiewicz
Nomogram
Developed in 2007
Prediction of RCC specific survival
Similar to UISS except ECOG performance status
is replaced by symptoms that distinguish
asymptomatic, local and systemic symptoms
Predictive accuracy – 89% (highest)
78

METASTATIC DISEASE
FRENCH GROUP
IMMUNOTHERAPY
MSKCC MODELS
79

FRENCH GROUP
IMMUNOTHERAPY
• 782 mRCC patients
• Factors – performance status, number &
location of metastases; interval between
diagnosis and systemic treatment; Hemoglobin
level, neutrophil count and other biological
signs of inflammation
• Designed to predict progression and survival
following cytokine based immunotherapy
• Stratified patients according to the number of
adverse prognostic factors into – good,
intermediate and poor risk with median survival
of 42, 15 and 6 months respectively
80

FRENCH
GROUP
IMMUNOTHERAPY
• Four independent factors predictive of rapid
progression under treatment
• Presence of hepatic metastases
• Short interval from RCC to metastases (<1yr)
• More than one metastatic site
• Elevated neutrophil counts
• Patients with atleast three of these factors –
0ver 80% probability of rapid progression
despite treatment.
81

MSKCC
MODEL
• 670 patients with advanced RCC who received
treatment with IFN alpha
• Retrospective study – to define pretreatment
features predictive of survival
• Five risk factos associated with shorter survival
• Low Karnofsky performance status (<80%)
• High lactate dehydrogenase (>1.5 times upper
limit of normal)
• Low serum hemoglobin (< lower limit of normal)
• High corrected serum calcium (>10md/dL)
• Interval from diagnosis to systemic treatment
(<1year)
82

MSKCC
• In addition to MSKCC criteria, prior radiotherapy and presence of more
than one site of metastases – negative prognostic value
GROUPS THREE YEAR
SURVIVAL
MEDIAN
SURVIVAL
FAVOURABLE RISK
(0)
31% 20 MONTHS
INTERMEDIATE RISK
(1-2)
7% 10 MONTHS
POOR RISK (>3) 0% 4 MONTHS
83

84

SUMMARY
• Wide spectrum of clinical
manifestations
• CECT – Gold standard in diagnosis and
staging
• Clinical TNM stage and Histological
grade – most important predictors of
prognosis
• Future – molecular biomarkers
85

THANK YOU
86

CLINICAL FEATURES & PROGNOSTIC FACTORS OF RCC

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