CAN DUAL ENERGY CT USING IODINE MAPPING PREDICT ...

CAN DUAL ENERGY CT

USING IODINE MAPPING

PREDICT THE NUCLEAR

GRADE OF CLEAR CELL

TYPE OF RENAL CELL

CARCINOMA

A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT

OF MD RADIODIAGNOSIS (BRANCH VIII) EXAMINATION OF

THE TAMIL NADU DRM.G.R MEDICAL UNIVERSITY,

CHENNAI TO BE HELD IN APRIL 2017

CERTIFICATE

This is to certify that the dissertation titled “Can dual energy CT using Iodine mapping

predict the nuclear grade of clear cell type of renal cell carcinoma” is the bonafide

work of Dr. Poulomi Mitra towards the MD Radiology Degree Examination of The

Tamil Nadu Dr. M.G.R Medical University to be conducted in April 2017. This work

has not been submitted to any university in part or full.

Dr. Shyamkumar N.K Dr. Anna Pulimood

Professor and Head Principal

Department of Radiology Christian Medical College

Christian Medical College Vellore 632002

Vellore 632004

CERTIFICATE

This is to certify that the dissertation titled “Can dual energy CT using Iodine mapping

predict the nuclear grade of clear cell type of renal cell carcinoma” is the bonafide

work of Dr. Poulomi Mitra towards the MD Radiology Degree Examination of The

Tamil Nadu Dr. M.G.R Medical University to be conducted in April 2017. This work

has not been submitted to any university in part or full.

Dr. Anu Eapen

Professor

Department of Radiology

Christian Medical College

Vellore - 632002

DECLARATION

I hereby declare that this dissertation titled “Can dual energy CT using Iodine mapping

predict the nuclear grade of clear cell type of renal cell carcinoma” is a bonafide work

done by me under the guidance of Dr. Anu Eapen, Professor of Radiology, Christian

Medical College, Vellore. This work has not been submitted to any university in part

or full.

Dr. Poulomi Mitra

Post Graduate Registrar

Department of Radiology

Christian Medical College Vellore

Vellore-632004

ACKNOWLEDGEMENT

This study would not have been possible without the help and hard work of many

people. It is practically not possible to acknowledge all of them separately by name in

short stretch. I wish to place in my record my sincere appreciation and immense

gratitude to some of them mentioned below.

First of all I would like to thank almighty God for guiding me althrough.

I sincerely thank to Dr Anu Eapen, my guide for guiding me throughout the study

period. I am deeply indebted to Dr Anuradha who was always ready to help and prompt

in response during the protocol development, IRB submission and results and analysis.

I would like to thank Dr. Betty Simon, who helped me setting the protocol. Dr. Ramani,

Associate Professor, Department of pathology patiently went through my proposal and

gave constant support in reading and interpreting pathological reports. Dr. Nitin Kekre

and Dr Antony Devasia and their team from Department of Urology provided all

necessary supports. I cannot forget the help of all the senior and junior radiographers

who worked relentlessly to put my project on the go. All my senior and junior

colleagues in the department helped me and supported me during this project.

I am grateful to Dr Visali Jayaseelan who helped me in analysis of results.

Last but not the least, my family, without their constant support this was not at

all possible.

CONTENTS: Page No

Abstract 09

Introduction 12

Aims 14

Objectives: 14

Review of Literature 14

Methods 46

Results & Analysis 55

Discussion 81

Conclusion 87

Limitation 87

Future Direction 87

Bibliography 88

Annexures 91

ABSTRACT

INTRODUCTION:

Renal cell carcinoma, most common malignancy of kidney is predominantly

disease of elderly. With a steady rise in global incidence of RCC number of

incidentally detected disease and small, localised diseases are also increasing. Other

than tumour stage, nuclear grade is considered an independent prognostic factor of

RCC. Recently introduced dual energy CT which uses two different peak energies

enables us to reconstruct virtual non contrast images, virtual monochromatic images

and two material (commonly iodine and water) decomposition and quantification.

AIMS:

The aim of the study is to see whether iodine concentration in the clear cell renal

cell carcinoma (RCC), obtained using iodine mapping in dual energy CT (DECT) can

predict the nuclear grade of clear cell type of renal cell carcinoma.

OBJECTIVES:

1 To correlate iodine concentration in clear cell type of RCC can predict the

nuclear grade of RCC.

2 To identify cut off values of iodine concentration which can best identify the

nuclear grade of RCC.

MATERIALS & METHODS:

It was a prospective study conducted during the time period of September 2014

to July 2016. Institutional review board approved the study. All patients with suspected

or known renal mass referred for pre-operative CT abdomen was recruited for the

study who underwent dual energy CT in arterial and venous phase in GE Discovery

750 HD CT machine. This is a single source fast kV switching dual energy CT

machine. Water suppressed iodine density images are obtained to draw ROI in three

different levels in RCC in both arterial and venous phases to get maximum, minimum

and mean iodine concentration. ROIs are also drawn in aorta and normal kidney in

arterial and venous phases. Post operatively histological types and nuclear grades were

noted. Finally, patients with clear cell type of RCC are included for analysis

RESULTS & ANALYSIS:

Total 95 lesions were analysed in 95 different patients. For three patients with

multiple RCCs larger lesion was considered for analysis. Predominantly cystic lesions

did not correlate well with nuclear grade. Solid tumours show good correlation with

nuclear grades. The mean iodine concentration in the venous phase showed maximum

correlation to predict nuclear grade. Mean venous phase iodine concentration of 16.74

mg/cc or less was found to predict higher grades of RCC (grade 3 and 4) with 65%

sensitivity and 81% specificity. Other factors which also show significant correlation

with nuclear grades are minimum venous phase iodine concentration, ratio of

minimum venous phase iodine concentration to mean iodine concentration in kidney

and ratio of minimum iodine concentration in arterial phase to arterial phase mean

kidney iodine concentration.

CONCLUSION:

The mean iodine concentration in the venous phase can predict nuclear grade

with moderate accuracy for solid tumours. For predominantly cystic RCCs iodine

concentration did not correlate with the nuclear grade.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common malignancy of kidney accounts

for 3% of adult malignancies and its incidence is steadily increasing throughout the

world at a rate of 2-3%. More than 50% RCCs are now being diagnosed incidentally,

due to sophistication of the imaging tools(1). With increase in incidentally detected

disease the number of localised and small disease are also increasing. Along with the

tumour size, local disease extent, and disease stage, nuclear grade is also considered

as independent prognostic factor for RCC. Fuhrman grading system which is based on

size, shape and margin of nucleus and prominence of nucleoli is now widely used to

grade RCC. Studies have shown that only 9.2% of small tumours are of high grade and

in a metaanalysis of 300 small RCCs 2-3 year follow up showed 2.8 mm growth rate

and only 4 had metastases(2). Because of these observations non- invasive or

minimally invasive treatment options are gaining popularity. Percutaneous renal

biopsies are also being used for planning management. Though renal biopsies are

almost 94% accurate in predicting histological subtypes, prediction of nuclear grade

with core biopsy is not reliable(3)(2). This led the investigators to look for non-

invasive ways to predict nuclear grade. Different CT findings and enhancement

patterns have been studied.

Dual energy CT is different from conventional CT that it uses two different peak

energies and is able to produce reconstructed virtual unenhanced images, virtual

monochromatic images and two basis material (mostly iodine and water)

differentiation and quantification.

In this study we aimed to measure iodine concentration in clear cell RCC and to

find relation with the nuclear grade of RCC.

AIMS

The aim of the study is to see whether iodine concentration in the clear cell renal

cell carcinoma (RCC), obtained using iodine mapping in dual energy CT (DECT) can

predict the nuclear grade of clear cell type of renal cell carcinoma.

OBJECTIVES

3 To correlate iodine concentration in clear cell type of RCC can predict the

nuclear grade of RCC.

4 To identify cut off values of iodine concentration which can best identify the

nuclear grade of RCC.

REVIEW OF LITERATURE

RENAL CELL CARCINOMA:

The most common malignant disease of kidney is renal cell carcinoma (RCC)

comprising of 85% of renal malignancies(1)

GLOBAL EPIDEMIOLOGY:

According to 2013 data, kidney cancer is the 15 th most common cancer in the

world and since 1990 its incidence has increased 107% in both the sexes. (4) This

increase in incidence is attributed by increase in incidence rate as well as increase in

life expectancy, both contributing equally to the overall increase in incidence(4). More

than 50% of RCCs are now being detected incidentally (1). With increase in

incidentally detected RCCs the number of localised disease or small lesions are

increasing. According to SEER (Surveillance Epidemiology and End Results)

statistics number of localised disease is 647% (5). This is predominantly the disease

of elderly, commonly occurring at 6-7th decade. Mortality in RCC is relatively low. In

UK 3% of cancer deaths are caused by kidney cancer in the year 2014. According to

the SEER statistics mortality rate has dropped consistently since year 2000 onwards.

INDIAN SCENARIO:

Incidence of RCC in India is less compared to the western world. Kidney cancers

rank 21st among all the cancers in India.(4). In a large retrospective study in India,

Agnihotri et al found younger age of patient at presentation and larger size of tumour

compared to the western population.(6)

CLINICAL PRESENTATION (1):

The classic triad of flank pain, palpable lump and haematuria are relatively rare

at presentation now a days and almost always indicate locally advanced disease.

Because of sophisticated imaging tools more than 50% of RCCs are now being

detected incidentally while undergoing imaging for other indications. Minority of

patients present with metastatic symptoms like cough and bone pain. An uncommon

but not worthy way of presentation is perirenal hemorrhage. So all patients with

perirenal hematoma with unclear etiology should be investigated to rule out under

lying renal cell carcinoma or angiomyolipoma.

Approximately 20% of patient of RCC have paraneoplastic syndrome which

include polycythemia, hypertension, hypercalcemia and Stauffer’s syndrome ie non

metastatic liver dysfunction.

PROGNOSTIC FACTORS:

Prognosis of RCC depends on the following factors(1)

1. Anatomic- Anatomical extent of disease or disease stage

2. Clinical- Patient’s performance, loss of weight, presence of paraneoplastic

disease

3. Histologic

- Tumour morphotype

- Nuclear grade of tumour

- Histologic necrosis

- Microvascular invasion

- Rhabdoid/ sarcomatoid differentiation

4. Different Molecular markers

1. TUMOUR MORPHOTYPE

RCC is basically adenocarcinoma arising from the tubular epithelial cell.

Recent investigations suggest that clear cell and papillary subtypes of RCC arise from

proximal convoluted tubules of nephrons, whereas all other histologic variants are

distal in origin. Since 1990, histological classifications of RCC underwent several

major modifications. The 2004, WHO classification changed the basic concept of

RCC, as a group of several different tumour subtypes, rather a single entity. Each

different subtypes has distinguished genetic basis and unique clinical features. The

latest classification is ISUP (International Society of Urologic Pathology) Vancouver

modification (2012) of 2004 WHO classification (7).

Table 1: Histological classification of RCC: Adapted from ISUP Vancouver

Modification of WHO (2004) Histologic Classification of Kidney Tumours

1. Clear cell carcinoma

- Multicystic clear cell carcinoma of low malignant potential

2. Papillary RCC

- Type I

- Type II

3. Chromophobe RCC

- Hybrid oncocytic chromophobe tumour

4. Carcinoma of the collecting ducts of Bellini

5. Renal medullary carcinoma

6. MiT family translocation RCC

- Xp11 translocation associated RCC

- t(6-11) translocation RCC

7. Carcinoma associated with Neuroblastoma

8. Mucinous tubular and spindle cell carcinoma

9. Tubulocystic RCC

10. Acquired cystic disease associated RCC

11. Clear cell (tubulo) papillary renal cell carcinoma

12. Hereditary leiomyomatosis and Renal cell carcimoa associated RCC

13. Renal cell carcinoma – unclassified.

Several reports suggests that clear cell RCC has worse prognosis compared to the

papillary and chromophobe subtypes. 5 year survival of clear cell RCC is 44-69%, for

papillary RCC is 82-92% and for chromophobe RCC is 78-87% (8). Presence of

sarcomatoid differentiation, collecting duct/ renal medullary origin and unclassified

RCCs have in general poorer prognosis On the other hand some tumors like

multiloculated cystic clear cell RCC and mucinous tubular and spindle cell RCC have

a documented indolent course.

2. NUCLEAR GRADE:

Grading of RCC is based on nuclear size, outline, presence or absence of nucleoli.

Fuhrman grading system has been widely accepted as a separate prognostic factor of

RCC.

Table 2: Fuhrman grade for clear cell carcinoma (1)

Nuclear

Grade

Nuclear Size Nuclear outline Nucleoli

1 10mm Round, uniform Inconspicuous or absent

2 15mm Mild irregular Small, visible at 400X

magnification

3 20mm Moderate to marked

irregular

Visible at 100X

magnification

4 >20 mm Bizarre, multilobed Prominent, heavy

clumps of chromatin

Fig 1 showing different nuclear grades of clear cell RCC(9)

Nuclear grade has been accepted as independent prognostic factor for RCCs

particularly for clear cell variant. In their original report in 1982, Fuhrman et al

reported 5 year survival of 64%, 34%, 31% and 10% for nuclear grades 1,2,3,4

respectively.

3. DISEASE STAGE & ROLE OF IMAGING:

In a case of renal space occupying lesion, the goal of imaging is to diagnose the

tumour and to assess the stage of the disease. According to the ACR appropriateness

criteria for pre-operative staging of RCC, CT abdomen with and without intravenous

contrast scores maximum with an adult effective radiation dose estimate ranging

between 10-30 mSV. A plain xray chest plays a complimentary role with CT. MRI

abdomen without and with contrast is the second choice in patients with iodinated

contrast allergy. Ultrasound has value in characterising a cystic renal mass and for

image guided biopsy of the renal tumour.

CT Protocol:

CT protocol for suspected or known renal tumour is not absolutely strict. Mild

variations in protocols are seen depending on the institute and author’s preference. But

all authors have recommended a non-contrast scan followed by administration of

iodinated contrast medium (100-150 ml of contrast containing 300mg/ml or 350mg/ml

of iodine) followed by image acquisition at corticomedullary and nephrographic

phases. (10)(11). Corticomedullary phase where contrast enhancement of cortex is

maximum can be acquired at 25-70 s delay and nephrographic phase where there is

homogeneous enhancement of renal parenchyma can be acquired at 100-120 s

delay.(12). A delayed phase or excretory phase (at 5-7 min delay) can be obtained to

complete urologic evaluation if requested by the clinician. Corticomedullary phase can

pick up early enhancing lesions where as some lesions become conspicuous in

nephrographic phase. Staging accuracy of 91% has been reported while using non-

contrast, cortico-medullary and nephrographic phases.

MDCT has an advantage over other CT as it can provide volume rendered data and 3D

reconstruction and maximum intensity projection images can be reconstructed, which

are of help for the clinician for planning surgery.

CT Findings:

In non- contrast images RCC has attenuation of 20HU or higher, difficult to

differentiate from normal renal parenchyma and only identified by focal cortical bulge

in most of the cases. Strong and heterogeneous enhancement is the classical finding in

RCC because of rich vascular supply. However in nephrographic phase RCC appear

hypodense compared to homogeneously enhancing parenchyma. Larger lesions are

usually heterogeneous owing to necrosis and hemorrhage and approximately 30%

RCCs show calcification (8).

CT plays an important role in differentiating RCC from other benign tumours

like angiomyolipoma (AML) and oncocytoma to avoid radical nephrectomy in benign

diseases. AML can be diagnosed with confidence by presence of intra-tumoral fat

content, However in approximately 4.5% cases fat content may be minimal and is

undetectable by CT. In those cases, homogeneous enhancement, prolonged

enhancement and hyperdense nature of the tumour in non-enhanced images can act as

a reliable guiding tool to diagnose AML. (8) Lee-Felker et al reported that absolute

HU value in unenhanced scan of more than 40 has 100% negative predictive value for

AML (13). The hallmark findings of oncocytoma are absence of necrosis, hemorrhage,

calcification; homogeneous contrast enhancement, central stellate scar and spoke

wheel appearance in a well marginated renal lesion. However it is difficult to diagnose

oncocytoma confidently on imaging. (8) Compared to oncocytoma clear cell RCC

shows absolute contrast wash out from corticomedullary to nephrographic phase and

significantly greater relative attenuation in the corticomedullary phase (13)

Bosniak et al classified cystic renal masses on CT.

Table 3: Bosniak classification system of characterising cystic renal masses(14)

Category CT Features and Proposed Management

I Simple cyst with thin wall, no septae or wall calcification or solid

component. It has attenuation of water with no enhancement

Intervention is not needed.

II Benign cystic lesion which may contain a few thin septae, fine

calcifications, or small segment of thick calcification in the wall

or septa

Or a uniformly high attenuated lesion (<3 cm), which show sharp

well defined margin and no enhancement in post contrast study

Intervention is not needed.

IIF Cysts showing thin septae, perceived but not measurable

enhancement of septae, focal wall or septal thickening or

calcification (which can be thick and nodular); no nodular

component present

Totally intrarenal, non enhancing, high attenuation lesions are

included

They are probably benign; however follow up is required

III Cystic mass with thick irregular or smooth wall or septae which

show measurable enhancement. Complicated, infected or

hemorrhagic cysts, multilocular cystic nephroma or cystic

neoplasms can be included in this group.

Usually requires surgery

IV Undoubtedly malignant features which include enhancing soft

tissue nodule within the cyst independent of the wall & septae

along with all other features described in type III

These lesions warrant surgical removal

CT scan plays a pivotal role in preoperative disease staging and guiding

management. Assessment of disease stage includes evaluation of the following (12)

i) Tumour size

ii) Tumour renal parenchyma interface

iii) Perinephric extension- involvement of Gerota’s fascia

iv) Involvement of pelvicalyceal system

v) Involvement of contiguous organs and adrenal gland

vi) Presence of venous involvement and extension

vii) Local and regional lymphadenopathy

viii) Local and distal metastases

Table 4: Modified AJCC staging of Kidney cancer (2010)

Primary Tumour

Tx Primary tumour cannot be assessed

T0 No evidence of primary tumour

T1 Tumour _< 7 cm, confined to kidney

T1a Tumour _< 4 cm, confined to kidney

T1b Tumour > 4cm and _< 7 cm, confined to kidney

T2 Tumour > 7 cm, confined to kidney

T2a Tumour > 7 cm and _< 10 cm, confined to kidney

T2b Tumour >10 cm, confined to kidney

T3 Tumour extends into major veins, perinephric spread, but no

extension beyond Gerota’s fascia and no involvement of adrenal

glands

T3a Tumour in renal vein or its segmental branches, perinephric or

renal sinus fat involvement, however no involvement beyond

Gerota’s fascia

T3b Tumour extending into the inferior vena cava (IVC) below the

diaphragm

T3c Tumour extends into IVC above the level of the diaphragm or

invades the wall of IVC

T4 Tumour extending beyond Gerota’s fascia

Contiguous involvement of adrenal gland

Nodal Disease

Nx Nodal involvement cannot be assessed

N0 No nodal involvement

N1 Any nodal involvement

Metastatic disease

Mx Metastatic disease cannot be assessed

M0 Metastasis is not present

M1 Non-contiguous involvement of adrenal gland

Other distant metastases

Stage Grouping

Stage I T1 N0 M0

Stage II T2 N0 M0

Stage III T1/2 N1 M0

Stage IV T4 Any N M0

Any T Any N M1

Assessing Perinephric Spread:

CT findings suggestive of perinephric spread includes indistinct tumour margin,

blurring of kidney outline, perinephric fat stranding,thickening of perirenal fascia and

perinephric nodules(12). Solid perinephric nodules are uncommon but definitive

feature of perinephric spread. Perinephric fat stranding is non-specific findings as it

can be associated with other inflammatory edema, fat necrosis, hemorrhage.

Hemorrhage is common in renal cancer and can mask or over-estimate perinephric

spread. Reports suggest that accuracy of detecting perinephric spread is low for both

CT and MRI. So all potentially locally advanced diseases are managed with radical

nephrectomy.

Assessment of Adrenal Gland:

Adrenal gland involvement cab be diagnosed with reasonable accuracy (100%

sensitivity and 76% specificity) with preoperative CT and per-operative findings.

Enlarged adrenal gland with indistinct margin and large renal tumour suggests adrenal

involvement.

Assessment of Nodal Disease:

Predominantly paraortic and renal hilar nodes are involved in nodal disease.

Though rare involvement of mediastinal and pulmonary hilar nodes are also reported,

more on right side because of direct communication with the thoracic duct (24).

Enlarged hilar or retroperitoneal lymph nodes more than 2 cm are almost always

metastatic. 43% false positive results are noted when 1 cm size criteria is used for

nodal enlargement. Incidence of reactive lymphadenopathy is higher in primary

tumour necrosis and IVC thrombosis. However CT has been reported to be 83-89%

accurate in predicting nodal disease.(12)

Assessment of Vascular Invasion:

The CT findings suggestive of venous involvement are distension of the vein,

abrupt change in venous calibre, intraluminal low density areas or filling defects.

Presence of collateral veins also support the diagnosis. Previously MRI was considered

to be superior in evaluating venous involvement. But recent data suggest multiplaner

CT can be equally helpful.

Assessment of Contiguous organ involvement & Distal metastases:

Direct involvement of the diaphragm, psoas, erector spinae, quadratous

lumborum by tumor are well seen in CT. Mere loss of fat plane with adjacent organs

such as liver and colon cannot be taken as contiguous organ involvement. The involved

organ should show definite change in attenuation and enlargement.(12). CT can show

lung, liver and bone metastases. Liver metastases are hypervascular and show arterial

phase enhancement. Bone lesions are expansile, lytic, can be seen in vertebrae, ribs

and pelvic bones. MDP Tc99 Bone scintigraphy is not sensitive for lytic bone

metastases and should be reserved for selected cases with bone pain, raised alkaline

phosphatase. Xray chest play complimentary role with CT abdomen to rule out

pulmonary metastases. CT thorax can be done with extensive intra- abdominal disease,

IVC thrombosis to rule out lung metastases. Resection of solitary pulmonary

metastases can improve 5 year survival from 26 to 56 %.( 24)

Table 5: TNM staging and 5 year survival of RCC

TNM (2009) 5 year survival (%)

T1aN0M0 90-100

T1bN0M0 80-90

T2aN0M0 65-80

T2bN0M0 50-70

T3aN0M0 50-70

T3bN0M0 40-60

T3cN0M0 20-40

T4N0M0 0-30

AnyTN1M0 0-20

AnyTN0M1 0-10

RECENT ADVANCES IN CT FURTHER CHARACTERISING RCC:

1. Predicting RCC subtypes in CT

Because of the known prognostic value of tumour morphotypes and nuclear

grades, different imaging parameters have been tested by several investigators to

predict the different subtypes of RCC. Various authors have suggested increased

enhancement and more heterogeneity in clear cell RCC compared to other subtypes

(15)(16)(17). Kim et.al reported significantly more attenuation value and degree of

enhancement in clear cell RCC compared to papillary and chromophobe variety in

both corticomedullary and excretory phases.(15) Same study mentioned a cut off value

for increase in attenuation by 84HU has 74% sensitivity and 100% specificity for clear

cell carcinoma. Clear cell RCCs are hypervascular and heterogeneous whereas

papillary and chromophobe RCCs are relatively hypovascular and more homogeneous.

In a recent retrospective study conducted in clear cell and papillary RCC who

underwent dual energy CT as part of pre-operative assessment, Mileto et al measured

iodine concentration in RCC. They concluded that iodine concentration of 0.9mg/ml

has 98.2% sensitivity and 86.3% specificity in differentiating clear cell from papillary

RCC. They also noted a significant correlation between the iodine concentration in

tumour and nuclear grade for both clear cell RCC (τ = 0.85; P < .001) and

papillary RCC (τ = 0.53; P < .001).

2. Predicting Nuclear Grade of RCC in CT

In 1994, after studying 100 renal cell carcinoma, Birnbaum reported that

tumour with higher nuclear grade are more likely to show larger size, more

heterogeneous appearance, indistinct margin and higher tumour stage; of which

tumour margin is more closely related to nuclear grade of tumour. In a recent

retrospective study on 48 patients Villalobos-Gollas et al concluded that lower

enhancing areas are negatively related with nuclear grade.(18) In another retrospective

study of 255 patients with clear cell carcinoma Zhu et al found that low enhancement

in corticomedullary phase has high association with high grade tumour. They also

concluded that relative enhancement in cortico-medullary phase in multiphasic CT

scan is the best predictor of grade tumour and it has 84% sensitivity and 93%

specificity when cut of value of 0.65 relative corticomedullary enhancement is

used.(19)

RECENT ADVANCES IN CT TECHNOLOGY:

With advent of multi detector row CT (MDCT) image acquisition has become

faster with acquisition of volume data, better multiplaner and 3D reconstruction, which

dramatically changed the radiologic imaging. Additional application of dual energy

CT technology enables further imaging analysis and advantage of material

differentiation and quantification

What is Dual Energy CT?

In contrast to conventional CT which uses polychromatic xray beam with single

peak energy (chosen between 80-140 kV), dual energy CT uses two peak energies.(20)

Two most frequently used energies in dual energy CT are 80 kV and 140 kV.

In dual energy CT, two different data sets are obtained from single anatomic

location, one with high energy and one with low energy. Because each material

behaves in specific way when exposed to different energy of xray photon their change

in attenuation is specific. Two materials which have similar appearance in one energy

can show significant attenuation difference at other energy. Like iodine and calcium

can have similar appearance in conventional CT, but at lower energies attenuation of

iodine is much more compared to the calcium.(21)

Dual energy CT principle is mainly based on the photoelectric effect of matter

when exposed to xray. At energies just above the k-shell binding energy (which is

specific for each material) of the element the element shows spike in the attenuation,

known as k-edge. Human body is mainly made of organic substances containing

hydrogen, oxygen, nitrogen, carbon and some inorganic substances like calcium,

phosphorus. Iodine, injected during post contrast studies show causes varying

enhancement of the structures depending on the vascularity because of its high

attenuation values compared to soft tissue. The k-edge values of carbon, nitrogen,

hydrogen and oxygen ranges from 0.01 to 0.53keV which are far below the xary

energies used in diagnostic imaging. K-shell energies of calcium (4.0keV) and iodine

(33.2 keV) are quite high compared to soft tissues in body and forms the basis of

material differentiation in dual energy CT scan.

DUAL ENERGY CT ACQUISITION:

The most commonly used energies are 80 and 140 kV because they allow

maximum spectral differentiation and minimum overlap. Five different ways of dual

energy image acquisition are possible

i) Sequential acquisition at two different energies in available CT machines

ii) Fast kV switching in a single tube DECT scanner – Prototype GE Discovery

750 HD

iii) Dual source dual energy CT- Prototype Siemens Somatom

iv) Layer detectors with single xray tube Protype Philips

v) Quantum counting or energy resolving detectors- not available

Each machine has unique way of acquiring and processing images and has their own

advantages and disadvantages

Table 6: Basic features of dual source DECT and single source DECT with fast kV

switching (22)(23)

Type of CT Scanner Dual Source DECT Single source DECT

Fast kV switch

No of tubes Two, arranged

perpendicular to each

other

Single tube

Detector rows Two Single

Field of view (FOV) Tube A= 50 cm

Tube B= 26-33 cm

Single tube with FOV 50

cm

Operations Two tubes work at

different tube potentials to

generate two different

data sets

Fast kV switching between

low and high energy

generates two data sets

Automatic current

modulation

Yes No

Iterative reconstruction to

reduce noise

SAFIRE / IRIS ASIR

Image recontruction Three material

decomposition (soft

tissue, fat, iodine) in

image space

Two material

decomposition (water &

iodine) in projection space

Post Processing Terms

VMC

Material specific Iodine

Images

Simulated unenhanced

images

Virtual Monoenergetic

(40-190)

Iodine maps (measured in

HU)

Virtual Unenhanced

(VUE)

Virtual Monochromatic

(40-140)

Iodine images (measured in

mg/ml)

Water images

SAFIRE= sonogram affirmed iterative reconstruction, IRIS=Iterative reconstruction

in image space, ASIR= Adaptive statistical iterative reconstruction

Table 7: Advantage of Disadvantages of different DECT scanners (22)(20)

ADVANTAGES DISADVANTAGES

DSCT Two xray tubes allow use

of separate filtration and

tube current modulation

to get better image

quality.

Relatively low overlap of

energies causing better

Limited temporal

registration as high

and low energy data

sets are not exactly

simultaneous

Limited FOV in tube

B. A body part may

signal to noise ratios in

reconstructed images.

Beam hardening

modifications can be

applied at image space

not be included

completely

Single Source,

Fast kV

Switching

Good temporal

registration because of

near simultaneous data

acquisition.

FOV-50 cm

Dual energy

reconstructions are

possible in both image

space and projection

space

Beam hardening artefact

reduction is possible in

calculated virtual

monochromatic images

Relatively higher

spectral overlap

resulting low spectral

resolution

Relatively high

radiation dose

because additional

dose limiting

techniques like

automatic tube

current modulation

and filtration are not

possible. (20)

Ours is a single source DECT which uses fast kV switching. Four sets of images

are obtained. These include a 140 kVp series that resembles a conventional CT series,

also known as the quality series; a virtual mono-chromatic images obtained with single

photon energy between 40 and 140 keV; a material-specific base pair series showing

low (ie, water) and high (ie, iodine) attenuating material(24).

DECT RECONSTRUCTION:

CT image reconstruction in a fast kV switching scanner occurs in projection

space. Two basic types of reconstruction can be done.

a) Material density images which gives material specific information.

b) Monochromatic images which give images at selected energy between 80-120k

Material Differentiation:

Generation of material density images is based on the theory that attenuation

coefficient of any material can be obtained by weighted sum of attenuation coefficients

of two basis materials as long as the k-edge of the material is not within the evaluated

energy range. The material pair should have significant difference in their effective

atomic number and their mass attenuation coefficients.

Depending on the clinical setting base material pairs can be chosen(25). The most

common material pairs used for material decomposition images are iodine-water and

iodine-calcium. The water density images in iodine-water material specific

reconstructed images can represent virtual non contrast images as it removes iodine

from reconstructed images. On the other hand in iodine density images in material

specific image sets show only iodine containing areas as high density areas and iodine

concentration is represented as mg/ml. Another important material is calcium which is

widely present in bones and plaques. Bone and calcium removal can play a significant

role in neurologic, cardiac and vascular imaging.

Fig 2 showing Colour coded iodine images (A) and Spectral HU curve (B)

Fig 3 showing Colour coded iodine images (A) and Spectral HU curve (B)

A B

A B

Fig 4A shows iodine suppressed water images (virtual unenhanced images) and 4B

shows water suppressed iodine images

Virtual Monochromatic Images:

Dual-energy CT scanners are able to generate virtual monochromatic (VMC)

images at any given kVp using complex algorithm resulting in images as if they were

imaged with a theoretical monochromatic beam. The appearance of images changes

with change in keV even if window width and levels are unchanged. The lower energy

images have higher contrast as well as more noise, and high energy images have less

contrast and less noise. So monoenergetic reconstruction should be done depending on

the clinical requirement. Matsumoto et al reported lowest image noise and improved

contrast to noise ratio in virtual monochromatic images obtained close to 70keV(26).

Reconstruction at 50-55keV has been reported to be better for evaluation of vessels

and slow flow or subtle endoleaks. High energy reconstruction at 95-150 keV can be

done to reduce metal artefacts depending upon the implant composition. It can be done

either is projection space or image space. Projection space reconstruction has

A B

additional advantage of reduced beam hardening artefacts and it provides curve

showing CT numbers (HU) of different materials against energy range of 40-

140keV.(25) Because of high attenuation of iodine at lower signal and improved

contrast to noise ratio lower dose of contrast dose can be used. These virtual single

photon–energy images provide more reliable attenuation values than conventional

polychromatic CT images.(27).However a single-energy CT scan using low tube

potential is superior to a dual energy scan with virtual monochromatic reconstruction

if material differentiation is not required(25)

Fig 5 shows virtual monochromatic images at 70keV, in venous phase (A) and

arterial phase (B)

RADIATION DOSE:

Radiation dose in dual energy CT depends on the technology. Initial reports by

Ho et al suggested 2-3 times increased radiation dose in DECT with single source fast

kV switching scanner(28). But image noise was not adjusted and image quality was

A B

not taken into account. Thomas et al conducted a phantom study using Alderson model

to characterise renal calculi using DECT showed comparable radiation dose with

SECT(29). Advantage of dual source system is, adjustment of the tube current and use

of separate filters can be done which will further reduce radiation dose to the patient.

Graser et al showed single phase acquisition using DECT can characterise renal mass

as benign or malignant accurately with colour coded images reducing the image

interpretation time and finally it reduced radiation exposure to patient.(30)

APPLICATIONS OF DECT IN GENITOURINARY DISEASES:

Song et al showed iodine overlay technique and using virtual non contrast images

can characterise renal masses as simple cysts, haemorrhagic cysts, angiomyolipoma

and RCC accurately. (31)

Graser et al showed single phase acquisition using DECT can characterise renal

mass as benign or malignant accurately with colour coded images reducing the image

interpretation time and finally it reduced radiation exposure to patient. (30)

Ascenti et al showed the value of virtual non contrast image and colour coded

iodine images in diagnosis of complex renal cysts. The use of virtual non contrast

images can obviate the need of the true noncontrast images and thus reduce radiation

dose. Color coded iodine images can pick up intra cystic enhancement effectively.(32)

Since DECT scanners are commercially available it has been used to characterise

renal stones into uric acid and non- uric acid stones. Recent in vitro studies could

successfully separate five different types of kidney stones ie struvite, cysteine, uric

acid, calcium- oxalate mono or dihydrate and hydroxyapatite/carbonate apatite using

DECT.

Brown et al reported the feasibility of using dual energy CT iodine overlay images to

differentiate a renal cyst from a solid enhancing lesion in a phantom model.(33)

Graser et al reported virtual unenhanced images can provide a reasonable

approximation of true unenhanced images and accordingly can lower radiation

exposure in patients with suspected renal disease.(24)

Ascenti G et al showed enhancement of renal lesions is important when

differentiating benign from malignant tumours. Dual energy CT offers measurement

of iodine uptake rather than mere enhancement values. Whole-tumour iodine

quantification seems more accurate than standard CT enhancement measurements.(32)

MANAGEMENT OF RCC:

Surgery is the mainstay of treatment in cases of renal cell carcinoma. Open/

laparoscopic partial nephrectomy, and open/ laparoscopic radical nephrectomy are the

available surgical techniques and can be selected according to the tumour size, renal

function. Those who are not good surgical candidates can be offered with other

ablation procedures and Active surveillance.

Partial nephrectomy:

Partial nephrectomy is the standard of care for all T1a diseases and it should

be offered to T1b patients also where technically feasible or where renal function is of

concern. If done in properly selected patients there is no significant change in outcome

compared to the radical nephrectomy.

Radical Nephrectomy:

Radical nephrectomy is the standard of care for T2 and higher stage diseases. In T1b

diseases also radical nephrectomy can be offered to patients after discussing the increase in

chances of CKD. Laparoscopic approach is preferred wherever feasible as it facilitates faster

recovery. Advanced stage like IVC involvement of disease doesn’t preclude surgical

management. Routine adrenalectomy and extensive lymph node dissection is not

recommended when there is no evidence of involvement in imaging or during surgery.

Ablative procedures:

Different ablative procedures like cryoablation, radiofrequency ablation can be

offered in patients with tumour size <3 cm. Compared to partial nephrectomy

recurrence rate is higher in this group and later on surgical management is more

difficult. However in elderly patients and patients with major surgical risks or

comorbidities, this offers an alternative treatment as it is minimally invasive.

Active Surveillance:

Several studies have suggested very no or minimal interval growth over the

period of 1-2 years in majority of localised RCC.(34). So this is a valid option in

sporadic, small incidentally detected RCC, particularly in patients who have limited

life expectancy or have other major comorbidities. Wehle et al have shown that if

surgery cannot be done due to comorbid illness or due to patient’s wish, incidentally

detected RCC <3.5 cm and with well differentiated histopathology can do well with

watchful waiting and regular CT scan without any surgery.(35)

Cytoreductive surgery & Metastectomy: Can be done to reduce tumour burden

Systemic Therapy:

Different systemic chemotherapy protocols can be offered to patients with

metastatic disease after prognosis stratification and depending on the response.

TREATMENT ALGORITHM (adapted from ESMO guidelines& AUA

guidelines)(36)(35)(37)(38)

Localised Diseases

Clinical T1a,

otherwise healthy

Standard-PN or RN

Option TA/ AS can be

discussed

Clinical T1a,

comorbidities, not a

good surgical

candidate

Thermal ablation (TA)

Or

Active Surveillance (AS)

Clinical T1b

disease, otherwise

healthy

Standard-RN Or PN where

feasible

Option TA/AS may be

discussed

Clinical T1b, major

surgical risks

Standard- RN

Recommendation- PN/AS

wherever possible

Option TA- increased risk

of local recurrence

Clinical T2 disease Laparoscopic RN

Locally advanced

T3/T4 disease

Standard- Open Radical nephrectomy.

- No role of systematic adrenalectomy or lymph

node dissection

Adjuvant Therapy- No proven role

*PN- Partial Nephrectomy, RN- Radical Nephrectomy, TA- Thermal Ablation, AS-

Active Surveillance

.

Role of Image Guided Biopsy:

Because of high diagnostic accuracy of modern imaging the role of renal biopsy

is limited if the patient is being planned for surgery. However it can be done in

following conditions (39)

1. Indeterminate radiological finding

2. Patients chosen/ willing for active surveillance

3. To know histology before starting ablative therapy

Metastatic Disease

Patient with

good

prognosis

Patient with

poor prognosis

Cytoreductive surgery

Systemic chemotherapy

Systemic

chemotherapy-

mainstay

Cytoreductive surgery-

No role

Metastatectomy- can be

considered

4. To select appropriate targeted therapeutic agent in patients with metastatic

disease

Core biopsies from solid renal tumours have very high diagnostic yield with

specificity 98-100% and sensitivity 86-100%. However very nuclear grading remains

challenging in core biopsy. Wang et al reported diagnostic accuracy as low as 46%.(3)

Overall, renal cell carcinoma can be considered as a heterogeneous group of

clinic-radio-pathologically different tumours. Each one is unique in clinical course and

prognosis. Fuhrman nuclear grade is another independent prognostic factor for the

renal cell carcinoma particularly of clear cell type. Different imaging findings has been

tested for assessing the type and grade of RCC. With the increase in number of

incidentally detected RCC, non-invasive/ minimally invasive way of typing and

grading appears to be the need of hour particularly in patients not a candidate for

surgery. Per cutaneous core biopsy can diagnose histologic type of RCC but core

biopsies cannot reliably depict nuclear grade. There are very few studies which had

attempted to correlate imaging findings with the nuclear grade.

With the above knowledge in mind we planned to correlate iodine concentration

in clear cell RCC using dual energy technique, with the Fuhrman nuclear grade of

RCC.

METHODS

STUDY DESIGN: Prospective

STUDY TYPE: Observational study.

This study was conducted in the department of radiology with collaboration with

departments of urology and pathology in Christian Medical College, Vellore.

STUDY PERIOD:

Patients were prospectively recruited from September 2014 to July 2016.

STUDY SETTING:

This study was conducted in the department of radiology with collaboration with

departments of urology and pathology in Christian Medical College, Vellore, which is

a tertiary care centre in south India with patients coming from all over India and also

from neighbouring countries like Bangladesh & Nepal. It has almost 2million annual

outpatient visits and in patient admission close to 130000.

STUDY POPULATION:

Inclusion Criteria:

All consecutive patients with known or suspected renal mass, referred for

preoperative CT scan and gave consent were initially recruited. However those who

underwent surgery in our institution during the study period and with histologically

proven clear cell subtype were finally included in analysis.

Exclusion Criteria:

Patients with known major contrast reaction and renal failure were excluded in

the study. Patients who were operated elsewhere or patients with renal tumour other

than clear cell RCC were also excluded from the study.

CT EXAMINATION:

CT Machine: GE Discovery 750 HD

CT Protocol:

Post contrast enhanced multiphasic CT was done using GSI (Gemstone Spectral

Imaging) mode.

Parameters used are fixed pitch of 0.9, mAs of 275-400 depending on the

patient’s thickness.

80 ml of non-ionic iodinated contrast was administered at a rate of 3ml/s using

dual chamber power injector followed by 10 ml saline flush.

Contrast tracker was used to trigger the post contrast scan.

Arterial phase scan was done once the contrast reached descending throracic

aorta. Venous scan was done at 35 seconds delay of arterial phase. Delayed scan

at 5 minutes was done in some patients as per referring clinician’s request but

GSI mode was not used for it.

Immediately following the scan 140 keV images appeared in the monitor which

were called QC (Quality Check) series. Afterwards monochromatic

reconstruction was done at 70keV for arterial phase and 60keV for venous

phase images. Reconstruction thickness used was 1.25mm

Fig 6 showing GE Discovery 750 HD CT

Fig 7 showing nonionic contrast agents used for intravenous contrast in CT

CT Evaluation:

Evaluation of CT images were done in PACS using coded proforma.

DECT Post Processing:

Dual energy post processing was done in GE AWHD workstation using ‘GSI

Volume Viewer’ software.

It generated paired sets of water and iodine images. Iodine concentration was

measured in the iodine images in mg/ml.

Regions of interest (ROIs) in the RCC at three different levels in both arterial

and venous phases. Out of the three ROIs drawn in RCC one was drawn at the

level of maximum tumour dimension. Areas showing calcific densities were

excluded. Maximum, minimum, mean iodine concentrations and the area of

ROI at each level noted down.

ROIs are also drawn in aorta at the level of kidney and in normal kidney. Only

the mean iodine concentration in aorta and normal kidney were noted down in

arterial and venous phases.

While processing the iodine-images spectral HU curve was also obtained which

shows attenuation values (HU) of aorta, normal kidney and RCCs at different

keVs. The HU value at the 40keV where the separation between the curves were

maximum, were noted down.

Fig 8 showing GE AWHD workstation

Fig 9A, 9B show monochromatic images of abdomen showing right kidney mass

suspicious of RCC

Fig 9C and 9D shows reconstructed water suppressed iodine images at arterial and

venous phases respectively. ROIs were selected in the RCC including maximum

diameter, aorta and and in normal kidney at the same level.

Follow up:

A B

C D

Patient was followed up till they have surgery or the limit of our time period.

Surgery, partial or radical nephrectomies were done in all the patients included

in final analysis.

Histopathological examination was done and reported in the department of

pathology.

Type of surgery done and histopathological findings as mentioned in coded

proforma were noted down.

VARIABLES:

Routine CT findings, Dual energy post processing data including Iodine

concentrations (Maximum, Minimum and Average) in RCC at three different levels as

well as mean iodine concentration in aorta and normal kidney. HU values at 40 Kev

where the separation of the curves are maximum were noted. Fuhrman nuclear grade

(1 to 4) of RCC were noted (details given in coded proforma)

DATA SOURCES:

Clinical workstation- basic patient details, CT report, pathology report

GE AWHD CT work station- dual energy post processing data

BIAS:

To avoid reporting bias post processing of dual energy images was done

immediately/ preoperatively. However the dual energy data was not be available to the

pathologist.

SAMPLE SIZE:

Sample size was calculated based on the results of the pilot study.

The mean iodine concentration in the RCC and the aorta in the arterial phase was used

for sample size calculation.

Standard Deviation in group I =9.5

Standard Deviation in group II =40

Mean Difference = 16 (Arterial phase mean iodine concentration in RCC compared to

aorta)

Effect size = 0.646464646464647

Alpha error (%) = 5

Power (%) = 80

Sided = Two

Required sample size per group= 104

QUANTITATIVE VARIABLES:

In RCC- maximum iodine concentration (Imax), Minimum iodine concentration

(Imin), mean iodine concentration (Imean) measured in arterial and venous phases

separately

In normal kidney- mean iodine concentration (Imean kid) measured in arterial

and venous phases.

STATISTICAL METHODS:

Mean with SD were evaluated for iodine concentration (arterial and

venous phases)

Mann Whitney U test was used to compare median iodine concentration

across the nuclear grades (1,2 vs 3,4)

ROC curve was plotted to find the best cut off for predicting the nuclear

grade

AUC (area under the curve) for iodine concentration was presented with

95% of confidence interval.

RESULTS & ANALYSIS

Total 140 patients with

suspected RCC underwent

DECT

No surgery was done is

26 patients

Surgery was done in 114

patients

Other than RCC (7)

RCC= 107

Clear Cell RCC = 95

Papillary RCC=1

Chromophobe= 5

Translocation

associated=4

Others = 2

ANALYSIS

Exclude

d

Exclude

d

Excluded

A. RESULTS SHOWING DEMOGRAPHIC DETAILS:

Total 95 patients were finally included for analysis with age range 25 to 72 years

and mean age of 49 years. There is definite male predominance with 73.7% of male

patients. 92 patients had single lesion. Three patients had multiple lesions, one of them

had two lesions on single side, one had one lesion on each side and one had total four

lesions distributed bilaterally. Patients with multiple lesions the largest lesion was

analysed. The lesions were almost uniformly distributed in right and left sides, 51.6 on

right side and 48.4% on left side. All the lesions were heterogeneously enhancing.

Table 8: Demographic Results

Number Percentage (%)

Sex

Male

Female

70

25

73.7

26.3

Number of lesions

Single

Multiple

92

3

96.8

3.2

Side of lesion

Right

Left

49

46

51.6

48.4

Table: 9 showing age of the patients presenting with different nuclear grades

Nuclear Grades 1 2 3 4

Number of

patients

18 59 15 3

Mean Age +/- SD 48+/-8.8 49+/-11 50+/- 10.1 58+/-10.1

Mean age of the patient was 48 years for grade 1, 49 for grade 2, 50 for grade 3 and

58 for grade 4 tumours. Overall mean age was 49 years.

c. Tumour Size:

Size of the tumour ranges from 1.25 cm to 15 cm in this study. Size of the tumour

showed significant correlation with the nuclear grade (p value= 0.009)

Table 10: showing correlation of the maximum tumour diameter with nuclear grade

Nuclear Grades

1

2

3

4

Tumour Size

(Mean +/- SD)

4.75+/- 2.4

7.03+/- 2.9

7.32+/- 2.7

11.05+/-

2.75

p value

0.009

B. RESULTS SHOWING CT FINDINGS IN DIFFERENT NUCLEAR GRADES OF RCC

Table 11: showing frequency of different CT findings

CT FINDING NUMBER PERCENTAGE

Nature Solid 84 88.4

Cystic 11 11.6

Margin Well defined 94 98.9

Ill defined 1 1.1

Necrosis Present 83 96.5

Absent 3 3.5

Percentage of

necrosis

< 25 % 38 46.3

25 – 75 % 41 50

> 75 % 3 3.7

Calcification Present 31 32.6

Absent 64 67.4

Renal vein

extension

Present 14 14.7

Absent 81 85.3

IVC extension Present 5 5.3

Absent 90 94.7

Part of IVC

involved

Infra-hepatic 5 100

Hepatic 0 0

Supra-hepatic 0 0

Lymph node

involvement

Present 12 12.6

Absent 83 87.4

Distant metastasis Present 5 5.3

Absent 90 94.7

Fig 8 showing frequencies of Nuclear grades of RCC in predominantly solid and

predominantly cystic diseases

Fig 9 showing presence of necrosis in different nuclear grades

15

53

14

236

1 1

0

10

20

30

40

50

60

Nuc Gr 1 Nuc Gr 2 Nuc Gr 3 Nuc Gr 4

Frequency of Nuclear Grades in Solid & Cystic RCCs

Solid Cystic

0

10

20

30

40

50

60

Nuc Gr1 Nuc Gr2 Nuc Gr3 Nuc Gr4

Frequency of Nuclear Grades with Necrosis

With Necrosis Without necrosis

Fig 10 showing presence of renal vein extension in different nuclear grades

Fig 11 showing presence of PCS invasion in different nuclear grades

0

58

1

18

54

7

2

0

10

20

30

40

50

60

Nuc Gr1 NucGr2 Nuc Gr3 Nuc Gr4

Freuency of Renal vein extension in different Nuclear

Grades

RV extension No RV Extension

2

21

7

1

16

38

8

2.8

0

5

10

15

20

25

30

35

40

Nuc Gr1 Nuc Gr2 Nuc Gr3 Nuc Gr4

Frequency Of PCS invasion in different Nuclear Grades

PCS Invasion No PCS invasion

Fig 12 showing presence of inferior vena cava (IVC) invasion in different nuclear

grades

Fig 13 showing presence of lymph nodes in different nuclear grades

02 3

0

18

57

12

2.8

0

10

20

30

40

50

60

Nuc Gr 1 Nuc Gr 2 Nuc Gr 3 Nuc Gr 4

Frequency of IVC extension in different Nuclear Grades

IVC extension No IVC extension

0

7

3 2

17

52

12

2.8

0

10

20

30

40

50

60

Nuc Gr 1 Nuc gr 2 Nuc gr 3 Nuc gr 4

Frequency of Lymph nodal Involvement in Different

Nuclear Grades

Lymph node present Lymph node absent

p=0.019

Fig 14 showing presence of calcification in different nuclear grades

Fig 15 showing frequency of distal metastases in different nuclear grades

3

12

0 0

14

47

15

3

0

5

10

15

20

25

30

35

40

45

50

Nuc Gr 1 Nuc Gr 2 Nuc Gr 3 Nuc Gr 4

Frequency of calcification in Different Nuclear Grades

Calcification No calcification

02 3

0

18

56

12

3

0

10

20

30

40

50

60

Nuc Gr1 Nuc Gr2 Nuc Gr3 Nuc Gr4

Frequency of Distal metastases in different Nuclear Grades

Distal Mets No distal mets

Fig 16 showing presence of lymphovascular invasion in different nuclear grades

Fig 17 showing perinephric fat infiltration in different nuclear grades

0

57

1

16

44

6

2

0

5

10

15

20

25

30

35

40

45

50

Nuc Gr 1 Nuc Gr 2 Nuc Gr 3 Nuc Gr 4

Frequency of Lympho-Vascular Invasion with Different

Nuclear Grades

LV invasion No LV invasion

0 03

1

14

49

62.8

0

10

20

30

40

50

60

Nuc Gr 1 Nuc Gr 2 Nuc Gr 3 Nuc Gr 4

Frequency of Perinephric Fat Infiltration in Different

Nuclear Grades

Perinephric Fat infiltration No perinephric fat infiltration

C. RESULTS OF UNIVARIATE ANALYSIS

Maximum, minimum and mean iodine concentration was measured both in

arterial and venous phases in RCC at three different ROIs. The median value of them

was calculated to measure the maximum, minimum and mean iodine concentration in

the tumour. Univariate analysis was done for parameters like maximum, minimum and

mean iodine concentrations in arterial and venous phase and their ratio with mean

iodine concentration of kidney in the same phase. Tumours were broadly divided into

the predominantly solid and predominantly cystic group and results of the univariate

tests are summarised in the following table.

1. For Solid Tumours

Table 12 showing mean +/- SD of iodine concentration related parameters in different

nuclear grades

Parameters

Nuc

Grade

No of

lesions

Mean +/- SD p value

I max Arterial Phase

1 14 76.2+/- 28.42

0.543 2 47 67.53+/- 17.87

3 12 66+/- 20.69

4 2 56.5+/- 2.12

I min Arterial Phase

1 14 -5.5+/- 8.67

0.082 2 47 -10.15+/- 9.9

3 12 11.92+/- 7.53

4 2 20+/-0

I mean Arterial Phase

1 14 32.15+/-15.61

0.084 2 47 25.38+/-12.95

3 12 20.42+/-5.78

4 2 13.32+/-2.62

I max Venous phase

1 15 49.4+/- 14.98

0.306 2 53 47.32+/-14.58

3 14 40.35+/-13.35

4 2 46.5+/2 2.12

I min Venous phase

1 14 -3.79+/- 6

0.032

2 52 -8.63+/-8.22

3 14 -9+/- 5.68

4 2 -19.5+/- 4.95

I mean Venous Phase

1 15 22.48+/-8.05

0.013

2 53 20.27+/-10.16

3 14 15.11+/-6.6

4 2 8.87+/-0.14

Ratio I max RCC/ I kid

In arterial phase

1 14 1.47+/- 0.44

0.508 2 47 1.58+/-0.39

3 12 1.89+/- 0.64

4 2 1.5+/-0.45

1 14 -0.14+/-0.18

Ratio I min RCC/I kid in

arterial phase

2 47 -0.28+/-0.27

0.042 3 12 -0.37+/-0.29

4 2 -0.53+/-0.14

Ratio I mean RCC/ I kid in

arterial phase

1 14 0.6+/-0.21

0.457

2 47 0.57+/-0.24

3 12 0.59+/-0.17

4 2 0.34+/-0.02

Ratio I max RCC/ I kid

Venous phase

1 15 1.09+/-0.32

0.566 2 53 1.11+/-0.27

3 14 1.07+/-0.22

4 2 1.3+/- 0.19

Ratio I min RCC/I kid

Venous phase

1 14 -0.099+/-0.15

0.032

2 52 -0.24+/-0.23

3 14 -0.26+/-0.19

4 2 -0.56+/-0.25

Ratio I mean RCC/I kid

Venous phase

1 15 22.48+/-8.05

0.082

2 53 20.27+/-10.15

3 14 15.10+/-6.6

4 2 8.8+/- 0.14

2. For Cystic Tumours

Table 13 showing mean +/- SD of iodine concentration related parameters in different

nuclear grades

Parameters

Nuc

Grade

No of

lesions

Mean +/- SD p value

I max Arterial Phase

1 3 52.67+/- 2.73

0.636 2 6 60.83+/- 16.21

3 1 61

4 1 65

I min Arterial Phase

1 3 -17.67+/-8.5

0.597

2 6 -15+/-8.31

3 1 -10

4 1 -25

I mean Arterial Phase

1 3 13.05+/-1.87

0.327 2 6 10.24+/- 6.27

3 1 23.13

4 1 7.36

I max Venous phase

1 3 42.67+/-11.02

0.563 2 6 35.67+/-10.41

3 1 47

4 1 51

I min Venous phase

1 3 -12+/- 9.54

0.428

2 6 -11+/-9.07

3 1 -15

4 1 -25

I mean Venous Phase

1 3 12.85+/-4.04

0.277

2 6 7.67+/-4.32

3 1 13.4

4 1 6.37

Ratio I max RCC/ I kid

In arterial phase

1 3 1.29+/-0.28

0.638 2 6 1.20+/-0.36

3 1 1.26

4 1 1.68

Ratio I min RCC/ I kid

In arterial phase

1 3 -0.46+/-0.26

0.327

2 6 -0.32+/-0.2

3 1 -0.21

4 1 -0.64

Ratio of I mean RCC / I

kidney in arterial phase

1 3 0.33+/-0.09

0.175

2 6 0.20+/-0.11

3 1 0.48

4 1 0.19

Ratio I max RCC/ I kid

Venous phase

1 3 1.09+/-0.23

0.467

2 6 0.85+/-0.31

3 1 0.91

4 1 1.31

Ratio I min RCC/ I kid

Venous phase

1 3 -0.33+/- 0.24

0.447

2 6 - 0.28+/- 0.23

3 1 -0.29

4 1 -0.64

Ratio I mean RCC/I kid

Venous phase

1 3 0.33+/-0.0.09

0.304

2 6 0.18+/- 0.11

3 1 0.3040.26

4 1 0.16

For solid tumours the minimum venous phase iodine concentration (vImin),

mean venous phase iodine concentration (vImean), ratio of minimum venous phase

iodine concentration to mean kidney iodine concentration (vImin/ vIkid) and ratio of

minimum iodine arterial phase iodine concentration to mean kidney iodine

concentration (aImin/aIkid) showed significant correlation.

For cystic tumours iodine concentration did not show significant correlation

with nuclear grades.

D. ANALYSIS OF ROC CURVES:

1.

Fig 18 showing ROC curve of the minimum iodine concentration in venous phase in

solid tumours

Minimum iodine concentration in venous phase predicted nuclear grade with an

accuracy of 0.635 (0.505 to 0.765), p value 0.125

AUC= 0.635

(0.505, 0.765)

p = 0.125

2.

Fig 19: showing ROC curve for Ratio of venous minimum iodine concentration in

RCC to mean kidney iodine concentration.

The ratio of minimum iodine concentration in venous phase to venous mean iodine

concentration in kidney predicted nuclear grade with an accuracy of 0.648 (00.509,

0.786) and p value 0.068

AUC=0.648

p value= 0.068

CI=0.509, 0.786

3.

Fig 20: showing ROC curve for venous mean iodine concentration in RCC

Mean iodine concentration in venous phase, in a case of solid tumours predicted

nuclear grade an accuracy of 0.730, ( 0.604, 0.857) and p value 0.004

AUC=0.730

(0.604-0.857)

p= 0.011

Fig 21 showing ROC curve for ratio of minimum arterial Iodine concentration in RCC

to mean arterial concentration of kidney

The ratio of minimum iodine concentration in arterial phase to arterial mean iodine

concentration in kidney predicted nuclear grade with an accuracy of 0.644

(0.477,0.811) and p value 0.094.

AUC= 0.644

().477- 0.811)

p=0.094

Fig 22 showing ROC curve for ratio of venous phase mean iodine concentration to

RCC to mean iodine concentration in kidney

The ratio of mean venous iodine concentration in RCC to the mean kidney iodine

concentration in a case of solid tumour predicted nuclear grade with an accuracy of

0.669 ( 0.540-0.799) and p value 0.036

AUC=0.669

CI= 0.540-0.799

p= 0.036

6.

Fig 23 showing ROC curve for ratio of venous phase maximum iodine concentration

in RCC to mean iodine concentration in kidney

The ROC curve shows that ratio of maximum venous phase iodine concentration in

RCC to mean iodine concentration in kidney, in a case of solid tumour does not help

in predicting the chance with nuclear grades.

AUC= 0.473

p= 0.741

Fig 24 showing ROC curve for ratio of arterial phase maximum iodine concentration

in RCC to mean iodine concentration in kidney

The ratio of maximum arterial phase iodine concentration to mean kidney iodine

concentration, in a solid tumour does not help in predicting nuclear grades.

.

AUC=0.399

p=0.242

E. RESULTS OF MULTIVARIATE ANALYSIS:

Multivariate analysis was done for solid tumours, between parameters like

minimum Iodine concentration in venous phase (vImin), mean iodine concentration in

venous phase (vImean), ratio of venous phase minimum iodine concentration to mean

iodine concentration in kidney (vImin/vImean kid), ratio of minimum arterial phase

iodine concentration to mean iodine concentration in kidney (aImin/aImean kidney),

ratio of maximum iodine concentration in arterial phase to mean iodine concentration

in kidney (aImax/aImean kid).

Table 13 showing multivariate analysis of significant parameters

Parameter Hypothesis

Wald 95% CI

B Std Error 95% CI Chi-square Df P-value Odds ratio for Exp(B)

vImin -0.117 0.1240 -0.360,0.126 .0.893 1.00 0.345 0.889 0.698, 1.134

vImean -0.226 0.0828 -0.388,-

0.063

7.412 1.00 0.006 0.798 0.679, 0.939

vImin/vImean

kid

6.868 4.8353 -2.609,

16.3445

2.018 1.00 0.155 981.417 0.074,

12551776.0

aImin/aImean

kid

0.660 1.9591 -3.180,4.500 0.114 1.00 0.736 1.935 0.042, 90.015

aImax/

aImeankid

1.992 0.8434 0.339, 3.645 5.578 1.00 0.018 7.329 1.403, 38.277

The two parameters that can best predict nuclear grades of RCC are the

1. Mean iodine concentration in venous phase Ratio of maximum iodine

concentration in RCC to mean iodine concentration in kidney in arterial phase

Among these mean venous iodine concentration is the most powerful because

of largest area under the curve and least 95% CI.

ROC Curves

1.

Fig 28 showing ROC curve for the mean venous iodine concentration.

Venous phase mean iodine concentration in solid tumours, can predict nuclear grade

with a moderate accuracy, area under the curve 0.73 (0.604-0.857).

AUC= 0.730

(0.604, 0.857)

p= 0.004

Venous phase mean iodine concentration with a cut off value of 16.74 or less can have

65% sensitivity and 81% specificity is predicting the higher nuclear grades of tumour.

DISCUSSION

With the steady increase in annual incidence of RCC, number of incidentally

detected tumours (>50%)(1) and number of localised (64%)(5) tumours are also

increasing. Surgery is the treatment of choice for all localised disease. However in

elderly patients, patients with significant comorbidity active surveillance of the disease

with periodic imaging is a valid option for treatment. Studies have shown only small

percentage (9.2%) of renal tumours are of high grade.

CT scan is the gold standard for assessing the anatomical stage of the disease.

There has been a continuous attempt to use different CT findings to correlate with the

other prognostic factors of RCC, like histological subtypes and nuclear grades.

In our study, we used post processed water suppressed iodine density images to

measure iodine concentration. Maximum, minimum and mean iodine concentration

was measured in both arterial and venous phases after selecting maximum possible

ROIs at three different levels of RCC (details given in methodology). Mean iodine

concentration in aorta and normal kidney was also measured for comparison.

We studied 95 different lesions in 95 patients. Three patients had more than one

lesions, among which the largest one was taken for analysis. Mean age of the patients

was 49 year with a range of 25-72years, which is less compared to the western

population. This supports Agnihotri et al who found relatively younger age of onset of

RCC in Indian population, contrast to the western population.

There was a clear male predominance with 73% patients being male. Equal

incidence of tumour was seen on both sides. Only 3 out of 95 patients (3.1%) of

patients have multifocal disease. Out of 95 lesions, 84 was predominantly solid, 11

were predominantly cystic.

The size of the solid tumour showed very strong correlation with the tumour

grade (p= 0.009). Higher tumour grades are more likely to have large tumour size.

Among other CT findings presence of lymph nodal involvement show significant

correlation with the tumour grade (p=0.019).

For analysis of the iodine concentration and its correlation with the nuclear grade

we split up the cases in predominantly solid and cystic. Overall these solid tumours

show good correlation with the iodine concentrations but the predominantly cystic

lesions fail to do so.

We found, a decreasing iodine concentration with increasing grade of RCC.

Though considerable overlaps are noted in iodine concentrations in Grade 2 and Grade

3 RCCs, it could reasonably separate high grade (grades 3, 4) from low grade (grades

1, 2) tumours.

The mean iodine concentration, minimum iodine concentration measured in

venous phase, ratio of minimum iodine concentration in RCC to that of kidney in the

venous phase as well as in arterial phase showed significant correlation with nuclear

grades of RCC.

Multivariate analysis was done between parameters which showed venous phase

mean iodine concentration in RCC can be the most powerful predictor of the nuclear

grade as it has the largest area under the curve. A cut of value of mean iodine

concentration in venous phase 16.74 or less has 64.7% sensitivity and 81.2%

specificity of predicting grade 3, 4 RCCs.

In recent study Mileto et al (40) showed iodine concentration in RCC has a strong

correlation with nuclear grades. They found increasing iodine concentration with

increasing nuclear grades. This difference is due to the methodology they applied.

They chose smallest ROI in the most enhancing parts of RCC after carefully avoiding

area of necrosis. Whereas in our study we included maximum area possible in ROI

including necrosis. Because necrosis increases with the increasing grade of tumour we

found the low iodine concentration values for higher grades.

However studies based on the enhancement pattern showed decreasing

enhancement with increasing grade. Villalobos-Gollas(18) et al concluded that lower

enhancing areas are negatively related with nuclear grade. In a another study Zhu et al

(19) analysed the enhancement pattern of clear cell RCC and showed increasing

nuclear grades with the decreasing enhancement of the tumour. They also suggested

cortico-medullary phase relative enhancement is the best predictor for nuclear grade.

In our study also ratio of arterial phase (cortico-medullary) maximum iodine

concentration in RCC to iodine concentration in kidney showed significant ability to

predict the higher nuclear grade. However, mean iodine concentration in the venous

phase appears to be most powerful predictor of the nuclear grade as it has larger area

under the curve. A mean venous phase iodine concentration of 16.74 mg/cc or less can

predict the higher nuclear grades (grades 3, 4) with 64.7% sensitivity and 81.2%

specificity.

Table 14: showing differences between our study and two closely related studies

Zhu et al Mileto et al Our study

Studied parameter Enhancement pattern Iodine quantification Iodine quantification

Study type Retrospective Retrospective Prospective

Methods Three ROIs as large as

possible in each phase

Vessels, calcification,

gross necrosis

excluded from the

ROIs

Average of three ROIs

was calculated to get

average enhancement

of the same phase

Homogeneous

lesions, ROIs placed

at maximum

transaxial diameter

Heterogeneous

lesions small ROIs

placed in maximum

enhancing part

avoiding the

necrotic area.

Three different

ROIs were drawn at

three different levels

One ROI at the level

of maximum axial

diameter

Necrosis not

excluded,

calcification

excluded.

Median values of

maximum,

minimum and mean

iodine concentration

calculated to get the

maximum,

minimum and mean

iodine concentration

of the tumour.

Results Corticomedullary

phase relative

enhancement- most

significant predictor.

Other important

predictors are cortico-

medullary phase

tumour enhancement,

nephrographic tumour

enhancement and

nephrographic relative

tumour enhancement

Increasing iodine

concentration was

found with increase

in the nuclear grades

Mean iodine

concentration in

venous phase

(nephrographic) is

the most powerful

predictor. A cut off

value of 16.74 or

less can be used

with a very high

specificity of 81.2%

The difference in results between the study done by Mileto.et al and our study is

due to difference is methodology as described. However our study results correlates

well with the study done by Zhu et al.

Overall, it is possible to differentiate between the high and low grade tumours by

measuring iodine concentrations.

Prediction of nuclear grade can help the doctors to determine the prognosis of

patients with multiple other comorbidities and put the patient on active surveillance.

Patients with multiple lesions or patients with syndrome associated RCC, where

nephron sparing surgery is of utmost importance, knowledge of approximate high or

low grade tumour can help surgeons deciding the resection margin.

Fig showing CT of a 28 year old man

with known case of VHL

A- A well- defined heterogeneously

enhancing partially exophytic

lesion in left kidney (arrow); Cyst

in the tail of pancreas( )

B- The tumour size was <4 cm

C- Reconstructed water suppressed

iodine image used for Iodine

quantification. ROIs drawn in

aorta, normal kidney and RCC

Partial nephrectomy was done which

showed grade 3 RCC. If prediction of

tumour grade is possible with iodine

concentration, a wider surgical margin

can be obtained.

C

A

B

CONCLUSION

Iodine concentration in clear cell type of renal cell carcinoma can predict high or

low nuclear grades of RCC. There is significant overlaps of values obtained for grade

2 and grade 3 diseases. Mean iodine concentration is the most powerful predictor of

nuclear grade with a cut off value of 16.7 mg/ml or less has 65% sensitivity and 81%

specificity of predicting higher nuclear grade.

LIMITATION

This study has some limitations

- It was conducted on a relatively small sample size.

- Relatively less number of high grade tumours, especially the grade 4 tumours.

- For predominant cystic lesions entire lesion was included in the ROI, leading to

unreliable iodine concentration in the tumour.

FUTURE DIRECTION:

With the use of dual energy technique it is possible to get reconstructed at images

at different keVs (between 40-140keV). Subtle enhancing lesions can become more

prominent lower keVs (compared to the tube potential used in conventional CT).

Contrast dose also can be reduced. Single phase acquisition with split bolus of contrast

can give useful set of images with relatively low radiation dose.

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ANNEXURES

1. IRB approval

2. Information sheet with consent form

3. Proforma

4. Data sheet

Department of Radiodiagnosis, Christian Medical College, Vellore

Study Title: Can Dual Energy CT with iodine mapping predict the Nuclear grades of

Clear cell type of Renal Cell Carcinoma

PATIENT INFORMATION SHEET

The following information is provided to inform you about this study and your participation

in it. Please read the information carefully and you are free to ask questions regarding the

study and the information given. Participation in this study is purely voluntary and you are

free to withdraw from the study anytime.

What is this study about?

This study aims to test the possibility of predicting the grade of renal cancer (RCC) before

surgery using a software in the CT (CT machine is called Dual energy CT).

What is dual energy CT? How it is different from the routine CT?

CT performed in dual energy CT scanner is same as any other CT. We will use a special

software to calculate amount of iodine in the kidney mass.

Is there any risk associated with this study?

As in routine CT, iodinated contrast material will be injected intravenously. Some patients

are prone to develop mild contrast reaction like itching, urticaria, running nose, sneezing,

dizziness, nausea. These symptoms usually resolve spontaneously with little or no treatment.

Severe reactions causing laryngeal edema, pulmonary edema, life threatening arrhythmia are

extremely rare. The risk of contrast reaction is same as that of other contrast enhanced CT

scans

Radiation is a known side effect of any study requiring Xray exposure. However there is no

additional radiation or additional risk to the patient for participating in this study.

If I take part in this study, what will I have to do?

Your CT scan abdomen is prescribed as part of your treatment protocol to know the stage of

your disease which will decide further management. This is the existing standard of care for

renal cancer patients. If you agree to participate in this study CT scan will be done using

dual energy CT scanner as per routine protocol and your medical records can be accessed by

the investigators of the study. No additional investigations will be done as part of this study.

The additional information obtained as part of the study will not be used to decide your

management. Your treatment will be as per routine protocol.

Can I withdraw from this study after it starts?

Your participation in this study is entirely voluntary and you are also free to withdraw

permission to participate in this study at any point. If you do so, this will not affect your

usual treatment at this hospital in any way.

Is there any benefit of the study?

There is no immediate benefit to you. However in future it may help the doctors to decide

management protocol of patients with renal cancer.

Will my personal details be kept confidential?

The results of this study will/may be published in a medical journal but you will not be

identified by name in any publication or presentation of results. However, your medical

record may be reviewed by doctors associated with the study, without your additional

permission.

If you have any further queries Please feel free to contact

Dr. Poulomi Mitra

PG registrar, Department of Radiology, CMC Vellore

Contact number: 0416228-3012/3609/3610 (Office), 09787628892 (mobile)

Email: [email protected]

Informed Consent Form Study Title:

Study Number: ____________

Subject’s Initials: __________________

Subject’s Name: _________________________________________

Date of Birth / Age: ___________________________

(Subject)

(i) I confirm that I have read and understood the information sheet dated ____________ for

the above study and have had the opportunity to ask questions.

(ii) I understand that my participation in the study is voluntary and that I am free to

withdraw at any time, without giving any reason, without my medical care or legal rights

being affected.

(iii) I understand that doctors working on the study, the Ethics Committee and the regulatory

authorities will not need my permission to look at my health records both in respect of the

current study and any further research that may be conducted in relation to it, even if I

withdraw from the trial. I agree to this access. However, I understand that my identity will

not be revealed in any information released to third parties or published.

(iv) I agree not to restrict the use of any data or results that arise from this study provided

such a use is only for scientific purpose(s).

(v) I agree to take part in the above study.

Signature (or Thumb impression) of the Subject/Legally Acceptable

Date: _____/_____/______

Signatory’s Name: _________________________________ Signature:

Or

Representative: _________________

Date: _____/_____/______

Signatory’s Name: _________________________________

Signature of the Investigator: ________________________

Date: _____/_____/______

Study Investigator’s Name: _________________________

Signature of the Witness: ___________________________

Date: _____/_____/_______

Name & Address of the Witness: ______________________________

PROFORMA

DEMOGRAPHY

Name: ________________________________ Hospital number: ________________

Age: ____________years

Sex: Male – 1; female – 0

CT FINDINGS:

Number of lesions: ________________

Laterality

1-Unilateral

2-Bilateral

Focality

1-Unifocal

2- Multifocal

Side

1-Right side

2-Left side

Maximum diameter of the lesion ____________ cm

Predominantly solid OR cystic

1- Predominantly Solid

2- Predominantly cystic

Margin:

1- Well defined

2- Ill defined

Enhancement:

1. Present

2. Absent

Pattern of enhancement

1- Homogeneous

2- Heterogeneous

Areas of necrosis:

1- Present

2- Absent

% necrosis:

1- <25%

2- 25-75%

3- >75%

Fat density areas:

1- Present

2- Absent

Calcification:

1. Present

2. Absent

Invasion of pelvicalyceal system:

1. Present

2. Absent

Extension into renal vein:

1. Present

2. Absent

Extension into IVC:

1- Present

2- Absent

If extension into IVC present

1- Infrahepatic

2- Hepatic

3- Suprahepatic

Lymph node enlargement

1. Present

2. Absent

Lymph node groups involved

1. Paraaortic

2. Parailiac

3. Others:

Distal metastases:

1. Present

2. Absent

Site of metastases:

1. Adrenals

2. Lungs

3. Liver

4. Bone

5. Brain

POST PROCESSING:

ARTERIAL

PHASE

Area Maximum

Iodine

Concentration

Minimum

Iodine

Concentration

Mean

Iodine

Concentration

ROI 1

ROI 2

ROI 3

Arterial phase Iodine concentration in aorta____________

Arterial phase Iodine concentration in kidney____________

VENOUS

PHASE

Area Maximum

Iodine

Concentration

Minimum

Iodine

Concentration

Mean

Iodine

Concentration

ROI 1

ROI 2

ROI 3

Venous phase Iodine concentration in aorta ____________

Venous phase iodine concentration in kidney____________

Spectral curve: Maximum HU at lowest KeV where there is maximum separation of spectral

curves

Aorta ____________

Kidney ____________

RCC

1. ____________

2. ____________

3. ____________

PATHOLOGY

Specimen obtained by

1. Surgery

2. Percutaneous biopsy

3. Fine needle aspiration cytology

Type of surgery

1. Partial nephrectomy

2. Radical nephrectomy

Lympho-vascular invasion

1. Present

2. Absent

Infiltration of perinephric fat

1. Present

2. Absent

Pathologic Type:

1. Clear cell renal cell carcinoma

Multilocular cystic clear cell renal cell neoplasm of low malignant potential*

2. Papillary renal cell carcinoma

Type 1

Type 2

3. Chromophobe renal cell carcinoma

Hybrid oncocytic chromophobe tumor

4. Carcinoma of the collecting ducts of Bellini

5. Renal medullary carcinoma

6. MiT family translocation renal cell carcinoma

Xp11 translocation renal cell carcinoma t(6;11) renal cell carcinoma

7. Carcinoma associated with neuroblastoma

8. Mucinous tubular and spindle cell carcinoma

9. Tubulocystic renal cell carcinoma

10. Acquired cystic disease associated renal cell carcinoma

11. Clear cell(tubular) papillary renal cell carcinoma

12. Hereditary leiomyomatosis renal cell carcinoma syndrome associated renal cell

carcinoma

13. Renal cell carcinoma unclassified

Nuclear Grade:

1- Fuhrman Grade 1

2- Fuhrman Grade 2

3- Fuhrman grade 3

4- Fuhrman grade 4

Data Sheet

Age in yrsSex No of lesionsLaterality Focality Side Max diameter cmSolid/ cysticMargin Enhancementenhancement patternNecrosis % NecrosisFat CalcificationPCS invasionRV extensionIVC extensionpart of IVC involvedPart of IVC involvedLN LN group Distal metastasesSite of metastasesSite of metastasessite of metastases

42 0 1 1 1 2 9 1 1 1 2 1 3 2 2 1 1 2 1 1 2

57 1 1 1 1 1 7.9 1 1 1 2 1 1 2 2 1 2 2 2 2

45 0 1 1 1 1 6.5 1 1 1 2 1 2 2 2 2 2 2 2 2

48 1 1 1 1 1 11.5 1 1 1 2 1 1 2 2 2 2 2 2

39 1 1 1 1 1 2.8 1 1 1 2 2 2 2 2 2 2 2 2

54 0 1 1 1 1 11.4 1 1 1 2 1 2 2 2 1 2 2 1 1 2

60 0 1 1 1 1 4.5 1 1 1 2 1 1 2 2 1 2 2 2 2

42 0 1 1 1 1 5 2 1 1 2 2 2 2 2 2

25 0 1 1 1 2 8 2 1 1 2 2 2 2 2 2 2 2

51 0 1 1 1 2 13.5 1 1 1 2 1 2 2 2 1 2 2 2 2

42 1 1 1 1 2 7.5 1 1 1 2 1 1 2 2 2 2 2 2 2

38 1 1 1 1 1 5.5 1 1 1 2 1 2 2 2 2 2 2 2 2

60 1 1 1 1 2 4 1 1 1 2 1 2 2 2 2 2 2 2 2

51 1 1 1 1 2 6.3 1 2 1 2 1 1 2 2 2 1 2 2 2

55 1 1 1 1 1 7.5 1 1 1 2 1 2 2 2 2 2 2 2 2

64 1 1 1 1 1 8.8 1 1 1 2 1 2 2 2 1 1 2 1 2 1 1 2

51 1 1 1 1 1 9.6 2 1 1 2 1 3 2 2 2 2 2 2

49 1 1 1 1 1 5.4 1 1 1 2 1 1 2 2 1 2 2 2 2

38 1 1 1 1 1 10.2 1 1 1 2 1 2 2 2 1 1 1 1 2 1 2

33 1 1 1 1 2 11.2 2 1 1 2 2 2 2 2 2 2 2

26 1 1 1 1 1 3.8 1 1 1 2 1 2 2 2 2 2 2 2 2

46 1 1 1 1 1 1.25 1 1 1 2 1 2 2 1 2 2 2 2 2 2

28 0 1 1 1 2 6.8 1 1 1 2 1 1 2 2 2 2 2 2 2

45 0 1 1 1 2 6.8 1 1 1 2 1 1 2 2 1 2 2 2 2

51 1 1 1 1 1 4.5 1 1 1 2 1 1 2 2 2 2 2 2 2

62 0 1 1 1 1 7 1 1 1 2 1 2 2 1 2 1 2 2 2

54 1 1 1 1 1 8.4 1 1 1 2 1 1 2 2 2 1 2 2 2

28 1 1 1 1 2 4.7 1 1 1 2 1 1 2 2 2 2 2 2 2

35 0 1 1 1 1 2.1 1 1 1 2 2 1 2 2 2 2 2 2

49 1 1 1 1 2 3.1 1 1 2 2 1 2 2 2 2 2 2 2 2

52 1 1 1 1 1 9 1 1 1 2 1 2 2 2 1 1 1 1 2 2 2

72 1 1 1 1 1 6.8 1 1 1 2 1 2 2 2 2 2 2 2 2

50 1 1 1 1 1 2.2 2 1 1 2 2 2 2 2 2 2 2 2

38 1 1 1 1 1 10.7 2 1 1 2 2 1 2 2 2 2 2

44 0 1 1 1 1 3.4 1 1 1 2 1 1 2 2 2 2 2 2 2

58 1 1 1 1 2 2.4 1 1 1 2 1 1 2 2 2 2 2 2 2

65 1 1 1 1 1 7.7 1 1 1 2 1 1 2 2 1 2 2 1 1 2

70 1 2 1 2 2 9.1 1 1 1 2 1 2 2 2 2 2 2 1 1 2

50 1 1 1 1 2 10.7 1 1 1 2 1 1 2 1 2 2 2 2 2

50 0 1 1 1 1 6 1 1 1 2 1 2 2 2 2 2 2 2 2

56 1 1 1 1 2 9.7 1 1 1 2 1 2 2 2 2 2 2 1 1 1 1

66 1 1 1 1 2 5.5 1 1 1 2 1 1 2 2 2 2 2 2 2

50 0 1 1 1 2 10.8 1 1 1 2 1 1 2 2 1 1 1 1 2 1 1 1 1

46 1 1 1 1 2 7.1 1 1 1 2 1 2 2 2 2 2 2 2 2

Site of metastasesA ROI1 areaA ROI1 ImaxA ROI1 IminA ROI1 ImeanA ROI2 areaA ROI2 ImaxA ROI2 IminA ROI2 ImeanA ROI3 areaA ROI3 ImaxA ROI3 IminA ROI3 ImeanA Imean AoA Imean KidV ROI 1 areaV ROI 1 ImaxV ROI 1 IminV ROI 1 I meanV ROI 2 AreaV ROI 2 ImaxV ROI 2 I minV ROI 2 I meanV ROI 3 AreaV ROI 3 ImaxV ROI 3 Imin

4757.9 71 -8 16.71 4180.9 61 -10 17.32 4900.9 67 -19 15.96 89.08 48.65 4908.7 31 -14 6.58 4528.6 31 -25 7.38 4928.5 36 -15

3477.2 114 -15 39.92 2706.5 109 -4 2210.3 98 -9 107.54 48.26 3324 41 -6 2218 37 0 20.71 3715.5 53 -11

2174.8 78 -6 19.83 1896.5 84 -9 23.63 2408.1 70 -8 19.28 83.76 39.84 2150.3 43 -24 14.25 2081 43 -6 16.48 2271.3 44 -10

3567.5 32 -10 10.44 3331.7 34 -12 11.74 3649.5 33 -2

322.6 74 17 49.98 312.4 68 10 39.96 355.5 70 4 42.07 100.6 53.61 335.4 50 -27 28.95 301 50 9 26.36 390.4 55 2

7089 127 -15 13.29 6531.5 76 -13 11.79 6704.4 108 -20 15.24 156.6 64.97 5969.1 48 7 18.05 6196.6 44 -15 12.24 6360.2 44 -6

995.6 82 -20 51.95 681.9 75 3 607.5 82 2 51.11 59.57 710.9 42 -8 27.95 689.2 46 13 27.79 815.7 48 1

1435.7 56 -8 8.92 1124.2 48 -6 10.89 1294.8 51 -14 11.63 154.7 50.86 1365.7 38 -3 8.7 1094.6 42 -2 11.67 1224.8 42 -3

3204.1 69 -12 5.4 3650 71 -9 4.59 3494.8 78 -10 4.47 153 71.12 3419.8 32 -6 5.55 3415.7 33 -5 4.55 3566.3 37 -18

2233.1 74 -6 19.45 1887.6 73 -9 23.07 1897.9 94 -7 36.45 118.5 42.38 2536.2 49 0 23.74 1863.8 46 -1 23.36 2470.9 49 -20

1165.8 61 -13 25.7 925.5 67 -23 24.46 849.8 65 0 34.72 91.21 41.23 1162.3 40 -6 17.82 946.9 39 -6 17.39 826.3 36 0

551.4 45 -3 20.98 551.4 51 -26 23.28 618.4 40 1

884 70 -2 32.55 925.5 71 -21 39.54 822.2 68 -4 34.28 103.8 38.95 1001.1 44 -2 23.37 879.5 41 -3 24.15 819.2 40 -13

2119.9 74 -28 21.14 1351.2 59 -28 19.61 1622.6 66 -23 17.95 106.7 52.67 2064.6 38 -18 13.16 1983 39 -26 14.71 1802 37 -19

3374.5 86 -11 30.96 2290.3 83 -14 20.46 1950.6 87 -9 30.99 96.5 52.22 4026.7 61 20.65 224.1 54 18.9 1575.2 58

2760.1 66 -25 31.41 3359.4 73 -14 30.35 1223.1 61 0 36.76 75.93 38.14 2965.5 43 -5 16.5 2901.1 37 -14 14.53 1623.4 32 -1

3620.8 60 -21 14.15 2439.2 58 -26 17.23 3086.2 51 -15 12.28 47.1 36.99 2854 34 -11 9.97 2213.2 32 -10 10.34 2867.7 26 -15

760 80 6 50.27 624.2 84 8 52.32 548.6 74 0 44.03 82.82 43.89 947 40 1 22.85 874.9 41 -4 24.53 876.1 41 7

3422.6 105 -13 38.48 3148.3 104 -11 43.6 4234.4 106 -13 29.08 95.4 48.95 3684.6 66 -20 30.07 3259 65 -15 32.88 3056.8 74 -12

4767.8 72 -19 14.93 4462.8 81 -19 14.32 4187.9 77 -17 20.93 80.11 45.14 5666.1 54 -16 11.26 3906.1 46 -10 13.36 4361 52 -10

740.5 63 34.52 346.4 55 27.35 695.9 65

27.2 49 4 24.42 13.8 32 1 17.96 26.9 35 4 13.52 77.26 59.84 20.04 49 4 24.42 24 32 1 17.96 34 4

1900.9 40 -12 12.06 2220.3 49 -16 11.15 1434.2 44 -7 16.54 101.2 42.08 2076.4 34 -9 14.78 1774.3 34 -11 10.48 1294.8 34 -5

1217.9 88 -3 35.21 1165.4 87 1 38.26 1034 84 -4 30.57 127.8 53.63 1574.3 65 1 31.32 1212.1 68 0 37.04 1345.1 60 -6

1253.8 90 8 46.76 1157.8 91 8 52.42 1255.2 80 -7 32.88 133.7 56.2 1535.6 69 -5 36.5 1045.6 80 7 42.92 1482.7 75 -18

2426.1 65 -12 21.61 2031.8 74 -9 31.81 2419.3 68 -17 22.18 68.91 30.53 2610 26 -27 6.43 2087.4 21 -8 10.68 2471.6 21 -12

2433.8 37 -20 11.42 1896.8 40 -21 9.37 2572.2 40 -20 11.13 74.19 19.37 2331.6 27 -15 10.41 1641.3 28 -8 9.09 1559.2 24 -1

613.5 63 -11 27.02 406.2 57 -2 25.69 519.7 71 -13 25.81 99.67 56.42 469.7 63 -13 17.48 373.7 68 -7 19.64 471.2 44 -8

114.3 34 -4 18.19 75.9 40 0 24.09 144.4 39 2 21.66 78.5 32.15 180.2 16 0 8.75 128.3 20 3 12.3 199.8 19 4

575 46 -15 11.44 636 42 -14 9.54 545.6 46 -9 14.85 89.14 47.4 575 27 -10 7.01 636 29 -11 6.15 515.8 27 -7

2351.1 66 -15 9.58 2405.2 75 -15 15.16 2174.3 71 -12 15.11 88.53 23.22 2354.8 22 -14 3.23 2231.2 30 -14 4.79 2214.3 31 -13

2598 22 -18 2.44 2429.4 20 -17 2.71 2351.8 24 -15 1.04 48.19 13.63 2591.6 21 -14 0.41 2412.1 23 -18 0.93 2628.1 22 -18

276.3 50 -10 10.51 151.1 36 -9 12.15 188.6 31 -5 9.55 72.9 34.69 128.1 19 -7 5.42 113.7 20 -8 6.7 279.6 31 -10

4515.7 58 -18 5.93 4267 71 -21 6.28 4569.1 87 -20 6.57 96.01 44.54 4854.4 34 -16 3.39 4918.6 34 -24 3.32 5191.5 78 -38

743.9 68 0 36.89 964 75 -13 34.29 671.1 65 -7

152.5 90 22 50.55 122.3 105 32 62.39 228.6 90 16 48.49 179.5 69.99 137.6 80 -22 42.99 122 88 39 61 152.5 81 13

3159.6 75 -10 26.04 2532.2 56 -5 26.35 3145.2 69 -12 27.98 85.02 40.62 2291.5 37 -5 19.87 3256 35 -3 19.15 2822.4 36 -7

3455.7 55 -20 15.17 2181.3 51 -5 18.53 4179.2 63 -27 6.82 79.22 46.57 3906.1 48 -16 7.93 3188.6 53 -15 13.06 4008.5 46 -20

3221.4 81 -20 16.27 3129.5 74 -22 19.63 2005.4 69 -13 16.6 96.74 44.26 2887.4 42 -10 15.56 3299 52 -8 18.77 2934.1 40 -11

1680.2 65 -22 19.27 1283.8 67 -8 24.26 1063.2 72 -10 29.76 95.78 42.94 1377.2 52 -6 20.55 1377.2 50 -3 19.95 1328.9 45 0

6201.1 76 -22 10.86 5259.3 57 -29 8.84 4417.3 74 -22 13.26 71.71 37.71 5992.9 54 -25 11.05 6079.9 66 -29 14.81 3708.4 53 -23

1386.3 57 -6 21.63 1083.2 46 -8 20.81 1490.6 46 -6 19.59 119.2 30.84 1737.3 42 -8 17.29 1525.7 45 -27 16.47 1297.2 39 -8

5088 31 -7 9.84 4148.9 38 -8 10.66 4544.4 28 -4

1865.8 77 -31 17.81 1857.4 75 -14 29.93 2217 78 -27

V ROI 3 ImeanV Imean AoV Imean kidA HU Ao A HU kid A HU ROI1A HU ROI 2A HU ROI3V HU Ao V HU kid V HU ROI1V HU ROI2V HU ROI3Specimen Surg type L-V invasionperinephric fat infilPath type Nuc gradelesion 2 sideMax dia solid/cyst Margin Enhancementenhancement typeNecrosis

7.45 25.16 31.82 739.1 360.3 154.9 129.8 177.5 245.1 302.2 83.8 93.6 91.8 1 2 1 2 1 2

27.58 31.97 1 2 2 2 1 1

15.91 28.55 39.02 718.4 408.5 182.3 223.4 207.7 265.1 295.6 143.4 158.1 165.7 1 2 2 1 2

12.56 25.31 26.8 237.9 244.3 117.6 115.9 136.4 1 2 2 2 1 2

27.07 28.86 38.62 864.5 485.7 469 403.1 379.3 280.4 350.4 270.9 251.6 239 1 1 2 1 2

15.87 50.58 56.53 1302.5 544.8 125.3 189.1 143 425.4 482.7 169.8 128.5 130.2 1 1 2 2 3

25.01 27.71 40.34 231.1 368.7 231.1 258.2 200.2 1 2 2 2 1 2

11.12 37.72 48.14 1303 437.7 101 127.5 104.8 345.6 435.2 95.6 70.7 75.4 1 1 2 2 1 1

5.26 49.52 63.56 1260.2 594.4 69.6 69.6 69.6 461.6 574.4 76.3 77.5 84 1 1 2 1 2

25.82 34.02 50.17 1004.6 372.9 184.8 372.9 335.4 323 435 215.1 213.6 230.3 1 1 2 2 1 2

20.74 28.61 36.21 768.1 360.2 234.2 228.1 307 264.6 320.9 172.5 162.9 195.5 1 1 2 1 2

22.62 23.27 28.3 232.2 340.9 195.5 213.9 206.4 1 1 2 2 1 2

16.51 29.54 32.25 869 335.7 289.9 351.1 283.7 272.8 287.3 162.2 218.1 167.6 1 1 2 2 1 2

11.7 31.49 36.5 884 384.5 206.5 158.3 184.5 271.7 305.6 133.6 140.9 121 1 2 1 2 1 3

22.36 43.04 63.13 1 2 2 2 1 1

15.96 28.55 26.11 702 375 296 272.9 227.2 242.1 237.1 160.7 140.4 166.3 1 2 1 1 1 3

7.57 21.46 29.63 223 264.6 93.3 82.2 82.2 1 2 1 1

24.73 33.8 45.9 719.3 381.6 259.3 287.1 396.5 298 334.8 217.9 232.3 268.1 1 2 2 2 1 2

28.6 47.02 71.56 465.2 655.1 331.3 346.8 386.9 1 2 1 2 1 2

16.33 30.76 37.39 719 376.3 138.4 165.8 188 261.4 407 166.3 98 124.7 1 2 2 1 2

29.98 41.59 60.65 425.2 527.5 293.3 257.2 272.4 1 1 2 2 1 2

25.87 25.88 39.42 631.3 534.1 412.3 353.8 441.3 234.2 326.6 130.8 189.3 204.7 1 1 2 1 1

15.1 42.12 50.14 860.6 407.1 129.5 130.1 156.4 373.6 431.8 131.5 128.8 165.2 1 2 2 2 1 2

29.09 40.92 48.29 1075 353 343.6 291.9 307.7 395 439.4 302 287.3 271.2 1 2 2 1 2

29.93 50.84 65.87 1 1 2 2 1 1

5.39 16.26 23.88 604.1 305.5 247.9 337.3 217.3 193.8 235.3 118.3 141.9 91.2 1 2 2 2 1 2

9.92 18.1 25.92 626 222.9 119.9 164.3 128.9 200 265 128 135 140 1 2 2 2 1 3

17.78 30.44 52.31 880 502.8 251.2 209.5 234.3 308 409.8 203.7 199.5 178.6 1 1 1 3

10.92 18.77 30.7 692 272.9 220.2 212.6 226 221.8 279.9 135.4 130.5 159.2 1 1 2 1 3

9.77 27.44 43.68 783.6 393.1 154.6 113.6 83.9 285 356.5 106 89.1 77.4 1 1 2 2 1 1

6.39 26.85 23.17 736.8 288 128.9 169.9 170 268 240.9 97.2 75.3 89.9 1 2 1 1 1 3

0.71 17.01 21.07 457.8 186.5 31.8 29 36 194.4 232 50.1 47.5 55.5 1 2 2 2 1 2 2

4.42 15.87 29.22 668.4 358 141 106 132.2 193 274.1 79.2 86.4 75.4 1 1 1 2

4.71 24.28 39.14 899.2 356.2 83.4 59.2 83.4 243.5 351.6 65.7 84.4 56.8 1 2 2 2 1 2

34.23 47.4 63.65 372.6 506.5 323.4 302.9 305 1 1 2 1 3

47.98 60.54 82.24 1 1 2 2 1 2

18.72 34.12 49.76 748.4 367.9 256.2 258.6 272.4 303.8 420.8 189.8 199.2 196.4 1 2 1 2 1 2

8.76 30.98 41.37 641.6 320.2 89.4 112.9 167.3 270.1 352.1 94.6 101.8 137.4 1 1 2 2 1 4

15.23 43.65 42.09 830 376.6 183.7 174.8 192.5 354.3 382.2 162.2 182.7 184.6 1 2 2 1 2

25.26 44.88 50.2 805 359.5 183.7 174.8 192.5 392.1 433.7 208.7 181.8 253.8 1 1 2 2 1 2

15.09 44.45 46.56 621.7 351.7 108.9 107.1 123.4 386.5 403.6 146.2 159.2 162.4 1 2 2 2 1 2

39 35.33 40.56 1001 277.7 194.9 180.4 196 315 355.7 178.2 157.1 172.4 1 2 2 2 1 3

9.86 42.24 34.46 379.6 303.3 128.2 135.6 150 1 2 1 2 1 3

21.12 45.94 65.15 1 2 2 2 1 2

58 1 1 1 1 2 9.6 1 1 2 2 1 2 2 2 1 1 1 1 2 2

66 1 1 1 1 2 3.4 1 1 1 2 1 2 2 2 2 2 2 2

57 1 1 1 1 1 7.2 1 1 1 2 1 1 2 2 1 1 2 2 2

48 1 1 1 1 2 13.5 1 1 1 2 1 2 2 1 1 2 2 1 1 2

38 0 1 1 1 2 2.8 1 1 1 2 1 1 2 2 2 2 2 2 2

52 1 1 1 1 1 7.1 1 1 1 2 1 1 2 2 1 2 2 2 2

48 1 1 1 1 2 14.2 1 1 1 2 1 2 2 2 1 2 2 2 2

62 1 1 1 1 2 7.3 1 1 1 2 1 1 2 1 2 2 2 2 2

46 0 1 1 1 2 5.7 1 1 1 2 1 2 2 2 2 2 2 2 2

61 1 1 1 1 2 5.8 1 1 1 2 1 2 2 2 2 2 2 2 2

53 0 2 2 2 1 4 1 1 2 2 1 1 2 2 2 2 2 2 2

57 1 1 1 1 1 7.3 1 1 1 2 1 2 1 2 2 2 2 2 2

46 1 1 1 1 1 14 1 1 1 2 1 2 2 1 1 2 2 2 2

60 1 1 1 1 2 4.4 1 1 1 2 1 1 2 2 2 2 2 2 2

67 1 1 1 1 1 5.6 1 1 1 2 1 1 2 2 1 2 2 2 2

52 1 1 1 1 2 15 2 1 1 2 2 2 2 2 2 2 2

36 1 1 1 1 2 4.3 1 1 1 2 1 1 2 2 1 2 2 2 2

36 0 1 1 1 2 9 2 1 1 2 2 1 2 2 2 1 1 2

49 0 1 1 1 1 8.9 1 1 1 2 1 2 2 2 2 2 2 2 2

66 1 1 1 1 2 5.5 1 1 1 2 1 2 2 2 2 2 2 1 1 2

57 1 1 1 1 2 4 1 1 1 2 1 1 2 2 2 2 2 2 2 2

53 1 1 1 1 2 13 1 1 1 2 1 2 2 2 1 1 2 1 1 2 1

48 0 1 1 1 2 7.2 1 1 1 2 1 2 2 1 2 2 2 2 2

38 0 1 1 1 2 2.4 1 1 1 2 1 1 2 2 2 2 2 2 2

40 1 1 1 1 1 4.7 1 1 1 2 1 2 2 2 2 2 2 2 2

50 1 1 1 1 1 7.3 1 1 1 2 1 2 2 2 2 2 2 2 2

53 1 1 1 1 2 3.8 2 1 1 2 2 1 2 2 2 2 2

54 0 1 1 1 2 3.5 1 1 1 2 1 1 2 2 2 2 2 2 2

54 1 1 1 1 1 5.6 1 1 1 2 1 1 2 2 1 2 2 2 2

30 1 1 1 1 1 3.6 1 1 1 2 1 1 2 2 2 2 2 2 2

45 1 1 1 1 1 8.3 1 1 1 2 1 2 2 2 1 2 2 2 2

49 1 1 1 1 2 7.3 1 1 1 2 1 2 2 2 1 2 2 2 2

42 1 1 1 1 2 4.8 2 1 1 2 2 2 2 2 2 2 2

34 1 1 1 1 1 4 1 1 1 2 1 2 2 2 2 2 2 2 2

36 1 1 1 1 2 3.4 2 1 1 2 2 2 2 2 2 2 2

41 1 1 1 1 1 6.6 1 1 1 2 1 2 2 2 1 1 1 1 2 2

32 1 1 1 1 1 3.7 1 1 1 2 1 1 2 2 2 2 2 2 2

47 1 1 1 1 1 10 1 1 1 2 1 2 2 1 1 2 2 2 2

55 0 1 1 1 2 7.5 1 1 1 2 1 1 2 2 1 1 2 2 2

57 1 1 1 1 2 6.7 1 1 1 2 1 3 2 2 2 1 2 2 1 1

61 0 4 2 2 2 12.4 1 1 1 2 1 2 2 2 2 2 2 2 2

54 1 1 1 1 2 10 1 1 1 2 1 2 2 1 1 2 2 1 1 2

50 1 1 1 1 1 3.3 1 1 1 2 1 1 2 2 2 2 2 2 2

53 0 1 1 1 1 8.5 1 1 1 2 1 2 1 1 1 2 2 2 2

63 1 1 1 1 2 6.1 1 1 1 2 1 1 2 1 2 2 2 2 2

51 1 1 1 1 1 8.3 1 1 1 2 1 2 2 2 1 2 2 1 1 2

53 1 1 1 1 1 5.7 1 1 1 2 1 1 2 2 1 2 2 2 2

48 1 1 1 1 1 4.6 1 1 1 2 1 1 2 1 2 2 2 2 2

72 1 1 1 1 1 2.9 1 1 1 2 1 2 2 2 2 2 2 2 2

52 1 1 1 1 1 8 1 1 1 2 1 1 2 2 2 2 2 2 2

62 1 1 1 1 2 3.7 1 1 1 2 1 1 2 2 2 2 2 2 2

2531.2 70 1 38.95 4048.6 73 -4 20.35 4131.6 77 -4 26.54 91.3 44.11 3483.7 44 -5 20.23 4219.5 42 -9 16.57 4127.6 34 -11

507.5 57 -7 25.07 565.4 44 -9 14.55 287.8 64 20 39.16 85.39 37.47 480.2 36 -9 12.42 309 40 -3 14.97 565.4 36 -10

1809.9 76 -3 40.79 1342.7 61 -13 25.01 1897.9 86 -10 41.96 98.44 40.79 1390.7 50 -8 23.29 1880.6 48 9 30.31 2141.7 49 -10

7381.6 59 -14 17.99 5336.7 80 -16 15.86 5804 58 -16 17.39 82.32 43.17 6469.5 46 -12 14.63 5750.7 44 -17 13.9 5295.3 40 -18

409.2 42 -8 10.65 232.5 50 -6 18.3 337.4 50 -9 11.4 74.96 35.83 312.3 63 3 24.59 359.2 48 6 23.88 292.7 46 3

1682.4 37 -18 11.13 2183 44 -16 13.61 1387.2 37 -7 15.95 74.61 40.04 1341.8 37 -9 11.27 2155 28 -8 11.25 1748.1 35 -10

7070.6 85 -17 16.13 3960 77 -24 22.45 8821.8 78 -33 11 98.36 43.19 9080.4 43 -21 10.52 7448.5 42 -11 10.2 8434.3 128 -12

2022.5 46 -14 12.4 1979 36 -10 12.96 1208.8 34 -5 14.12 85.25 39.61 2658.8 35 -19 15.22 2014.1 35 -4 14.99 1297.3 32 -2

1241.7 74 -6 21.47 1549.9 64 -16 22.08 1273.4 59 -12 20.47 96.62 34.61 1887.1 44 -6 16.25 1579.1 40 -6 16.92 1625.5 46 -5

1156.2 61 -7 15.87 1595.4 46 -14 16.35 1235.4 58 -12 17.29 77.04 33.42 1746 53 -18 15.07 1465.2 41 -12 12.43 1361.8 49 -18

568.7 97 -1 58.32 370.7 102 -1 54.24 631.7 92 -4 59.37 143.2 62.56 629.8 68 12 49.4 920.1 76 -11 50.03 864.9 78 -7

1481.2 126 -7 50.99 1484.6 122 -12 41.14 1418.9 107 -10 50.31 135.7 65.24 1628 61 -5 28.07 1106.9 59 -3 32.95 2452.4 53 -6

5657.9 75 -22 17.65 5573.6 82 -21 18.05 3614.1 77 -20 19.04 93.68 51 4307.9 49 -21 13.19 5461.3 56 -21 12.73 3875.6 51 -17

686.2 39 -21 11.58 538.5 49 -6 19.89 451.2 58 -14 22.84 78.34 35.02 584.9 43 -5 20.29 562.8 47 2 20.63 566.2 43 -10

2183.3 74 -26 30.16 1972.8 64 -8 23.43 1537.4 73 -8 33.89 100.4 64.22 2085.5 66 -13 26.19 1938 62 -3 26.85 1746.6 71 -5

7954.9 65 -16 7.36 5796.6 87 -25 11.21 11220.6 62 -33 2.89 84.05 38.79 11162.9 57 -25 6.37 6311.4 47 -16 11.11 12660.4 51 -27

604.8 42 -13 7.75 409.2 45 -12 11.59 541.2 36 -10 10.16 79.69 35.97 408.7 35 -2 15.54 677.3 37 -5 15.34 707 36 -22

3260.5 80 -22 4.95 4054.1 46 -27 5.01 4918 41 -29 4.34 73.55 45.15 5246.7 53 -23 5.65 3902.5 40 -13 6.22 6484.9 40 -19

4384.7 110 -13 41.22 3764 109 -15 48.34 4086.6 110 -28 35.38 110.1 49.63 4649 74 -2 42.58 3762.2 77 5 42.78 4109.2 80 -12

1389.2 62 -12 28.99 1295.3 73 -14 26.45 1433.7 64 -22 26 93.01 33.7 1435.2 38 -8 19.16 1337.8 44 -6 17.23 1324.5 41 -8

3839.9 79 -38 2.61 3428.9 35 -36 2.19 3652.8 38 -34 1.37 84.04 45.59 4023.3 32 -35 4.04 3735 30 -28 3.43 2880.6 39 -29

7603 53 -20 10.58 9332.7 64 -30 11.46 5251.4 58 -13 13.96 72.6 31.87 7381.2 46 -23 14.66 10234.8 45 -28 8.96 8517.8 39 -22

1359.6 67 -12 32.11 1949.4 74 -14 28 2358.7 66 -11 21.11 105.15 40.07 1992.9 49 -2 26.28 2292.5 59 -9 23.2 2214.3 52 -8

161.1 95 9 50.81 160.1 90 3 52.99 219.7 102 10 51.7 78.59 72.64 224.8 54 -3 27.59 155.1 58 9 33.47 142.2 64 -3

1548.4 88 -12 35.5 1224.5 85 -17 32.84 1224.5 85 -11 70.46 51.79 54.79 1526.2 56 -16 17.95 1317.7 62 -17 15.78 833 44 -5

2024.9 65 -23 26.05 2644.3 68 -4 31.22 2568.9 67 -22 19.62 58.75 38.27 2092.2 59 -13 24.06 3354.1 47 -25 17.29 2293 48 -17

551 44 -27 12.36 450.2 54 -22 14.1 313.4 49 -24 15.6 74.01 37.25 486.4 54 -27 17.47 602 59 -15 13.76 486.4 51 -22

778.7 65 -5 31.53 515.8 72 0 37.65 643.2 69 -15 29.23 129 30.92 811.8 72 3 30.81 849.8 71 -8 30.05 643.2 53 -10

1796.1 80 -20 26.59 1923 74 -13 28.32 1617.1 69 -35 20.21 74.85 32.18 1796.1 54 -32 21.14 1927.1 66 -10 24.41 1078.7 63 -15

752 84 -8 38.22 724.5 80 -10 34.22 506.9 85 0 44.19 103.4 66.07 613.5 78 -5 36.45 611.6 71 3 33.69 613.8 62 0

1994.8 83 -18 19.9 2293 83 -18 19.9 1577.6 74 -6 27.17 74.82 40.49 2231.2 54 -12 17.46 2223.2 47 -17 16.49 1824.8 45 -13

3083.5 59 -23 41.18 3207.4 54 -8 26.98 2681.9 52 -4 25.22 41.18 39.89 3050.5 23 -21 4.48 2971.5 24 -15 4.69 2684.3 24 -21

1168.7 57 -14 10.96 845.9 64 -10 23.13 815.7 61 -7 29.68 109.2 48.45 1165.3 51 -15 12.86 1128.7 47 -15 17.8 1005.6 46 -16

1159.3 53 -11 14.7 1149 56 -12 17.92 777.7 77 -13 19.27 97.32 51.82 1108.6 36 -9 13.82 733.2 30 -1 14.25 930.6 34 -9

850.3 64 -5 20.17 1004.4 72 -3 17.36 900.3 56 -7 20.22 87.38 75.01 746.5 35 -3 12.95 742.1 38 1 13.72 642.2 27 1

1531 90 -12 25.12 1123.7 92 -8 29.35 1002.6 96 -11 53.96 93.53 40.04 1390.7 44 -3 16.94 1582.7 49 -4 26.44 884.5 47 4

599.4 41 15 26.59 666.2 39 -2 25.48 904.5 35 -9

5258.8 46 -16 54.91 4789.1 51 -14 17.95 3129.9 52 -18 14.55 54.91 38.12 4999.7 33 -7 11 3813.9 32 -5 10.91 2237.2 53 -5

1934.5 95 -15 19.97 1903.4 98 -6 22.57 2050.7 96 -2 23.7 100.4 35.33 1786.7 37 -10 13.91 1994.8 40 -6 14.84 1578.1 33 -2

1898.4 75 -14 19.33 1626.5 70 -4 21.2 3046.4 56 -13 10.74 103.9 25.37 2045.8 35 -2 14.12 1414.4 35 -18 16.85 2768.6 39 -114

7236.6 55 -19 6.31 7120.6 66 -27 8.11 5873.3 59 -22 4.75 50.42 30.15 7623.9 31 -18 1.99 7360.5 31 -19 4.02 5272.4 41 -28

4080.7 53 -18 19.1 3703.4 46 -8 18.16 3869.1 45 -12 13.53 82.53 36 4105.9 29 -12 13.57 4054.9 39 -11 14.18 3950.1 31 -10

778.7 66 -15 32.58 544.1 49 9 29.82 560.9 58 7 30.24 117.6 64.88 715.9 56 -8 27.72 573.5 56 7 29.21 711.4 44 8

3852.7 68 -3 17.3 3774.6 49 -3 15.74 2792.3 57 -4 19.4 119.2 41.51 3267.9 63 -6 18.48 3689.6 33 -4 17.58 2917.4 37 -4

2 1532.7 52 -30 18.41 1237.2 51 0 23.34 1501.8 51 -13

4162 54 -14 17.76 2810.6 48 -11 19.54 3620.7 54 -10 17.24 67.49 26.6 3614.7 52 -10 16.13 3540.5 54 -15 17.87 3442 48 -14

2089 72 -5 16.33 1800 51 -6 14.95 2089 64 -7 21.08 113.4 49.74 1924.2 52 0 20.08 1919.1 44 -12 15.91 1707.5 47 2

674.8 66 11 39.88 455.9 63 9 37.84 649.1 61 -11 37.06 92.92 57 771.7 51 -18 29.8 455.6 48 1 30.98 749.5 52 0

314.9 59 3 25.99 314.2 44 -1 20.98 273.3 59 3 25.99 91.97 46.88 360.8 58 0 25.64 292.7 53 -6 23.06 381.3 57 1

3874 40 -3 16.55 3579.3 36 -2 16.85 4481.1 43 -25

470.4 121 -8 51.83 724.2 119 -6 59.35 533.9 119 0 60.2 108.6 64.2 586.5 97 0 33.18 621.1 77 0 33.2 519.9 76 4

12.99 30.25 36.57 747.3 348.5 317.8 213 258 282.1 327.8 220.4 155.1 187.6 1 2 1 1 3

18.68 31.87 43.48 723.4 408.4 150 289.6 137 288.1 358.9 158 257.7 139.9 1 1 2 1 1

27.1 38.69 23.29 825.3 327.7 369.7 369 338.9 351.4 379.7 270.8 251.7 238.1 1 2 1 2 1 2

14.72 32.86 42.16 698.3 375.5 178.2 165.7 169.3 287.5 345.2 146.9 159.7 160.7 1 2 2 2 1 2

24.67 41.32 55.49 637 295.6 113.1 136.5 136 367.6 476.9 233.3 224.9 250.5 1 1 2 2 1 1

12.08 26.19 26.38 648.4 333.2 168.5 201.7 143.7 251.4 331.7 126.7 127.4 130.8 1 2 2 2 1 2

9.91 35.87 53.59 835.5 426.9 95.6 120.1 154.4 307.3 433.6 102.2 127.1 109.7 1 2 1 2 1 2

14.17 29.74 38.22 700 286.1 134.2 152.2 124.6 282.7 335.6 159.7 157.7 168.3 1 2 2 2 1 2

18.05 35.84 34.5 817.2 311.1 215.8 209.4 224.7 309.1 255.6 176.7 167.6 167.6 1 2 2 2 1 1

17.38 31.45 32.29 691.3 235.7 99.8 165.2 160.9 305 315 144.6 135.2 131.1 1 2 2 1 2

52.11 70.78 51.16 1198.8 601.6 392.3 495.6 462.1 470.8 589.3 449 435.9 429.1 1 1 2 1 2

28.54 47.5 55.18 1149.7 535.2 438.5 400.4 479.4 413.5 515.1 258.3 274.4 284.2 1 2 2 2 1 1

11.82 37.29 43.24 778.2 434.1 183.2 146.4 109.6 328.1 394.1 134.1 139.3 87.9 1 2 2 2 1 2

24.21 37.37 46.18 670.4 265.3 120.4 204 171.2 329.3 397 261.9 277 202.1 1 1 2 2 1 2

32.31 50.09 76.48 883.5 486.1 244.2 219.5 305.1 444.2 587.2 244.3 250.9 292.7 1 2 2 2 1 2

4.88 47.36 39.04 718 330.8 73.5 82.5 50.4 407.7 359.5 83.3 99.7 41.1 1 2 2 1 4

13.28 24.92 33.62 632.7 309.4 96.5 134.2 120.9 229.2 292.1 128.2 155.2 159.3 1 2 2 2 1 2

4.37 36.72 41.34 657 350 53.9 53.4 69.6 315.4 373.4 72.3 53.5 76.9 1 2 2 2 1 2

31.39 47.47 54.33 926.9 435.7 438.7 454.2 304.5 401.4 463.8 364.5 293.3 282.8 1 2 2 2 1 2

17.56 34.16 33.19 796.6 272.3 262.5 281.3 283.7 300.1 310.8 179.6 166.5 178.5 1 2 2 2 1 2

3.33 32.23 42.97 641.3 297.8 91 102 137.4 229.3 397.6 154.1 154.9 127.7 1 1 2 1 2

8.02 27.62 31.25 630.8 263.6 127 148.3 130.3 258.3 289 105.6 148.9 110 1 2 1 1 1 4

23.56 38.09 50.02 883.9 384.1 313.3 384.1 200.9 350 435.7 234.1 221.6 250.4 1 2 2 2 1 2

26.57 46.12 75.97 685 731.7 397.3 434.8 425.8 415 582.2 306.5 282.2 269.1 1 1 2 2 1 1

21.45 31.3 35.95 483.3 453.4 483.3 465.8 356.8 314.8 333 190.5 166.1 210 1 1 2 2 1 1

14.79 24.83 39.12 506.5 367 252.1 297.6 175.4 236.7 326.8 180 220.6 139.6 1 2 2 1 2

18.67 31.42 40.59 650 323 145.8 139.8 108 279.2 212.8 122.5 161 127.4 1 1 2 1 1

24.48 45.6 56.33 1024 367.1 333.8 283.1 273.1 420.9 515.2 288.8 299.8 249.8 1 1 2 1 2

24.62 29.18 34.33 679.6 312.1 275 252.2 194.2 312.7 291.8 210.8 224.4 175.1 1 2 2 2 1 2

33.19 38.02 48.2 933.6 570.4 351.4 310.9 357.2 340 501.1 289.8 327.7 322.2 1 1 2 1 2

17.5 35.06 37.06 648 351.7 226.4 233 216.2 296.5 325.9 162.6 167.4 179.8 1 2 2 2 1 2

3.42 15.2 24.04 1 2 2 2 1 2

13.4 45.82 51.75 914 399.7 266.5 329.8 86.4 352 446.3 201.7 247.9 109.7 1 1 2 2 1 3

11.87 32.89 47.37 873.8 430.9 157.2 152.5 149.5 297.8 387.3 125.2 149.4 121.8 1 2 2 1 2

12.73 37.67 53.14 749 632.7 176.7 134.5 171 343.5 475.3 131.6 121.8 116.6 1 2 2 2 1 2

31.21 36.04 44.35 794.8 341.6 299.5 229.1 225 349.4 400.7 189.9 250.9 167.4 1 2 1 2

23.32 30.73 35.7 282.5 307.8 233.8 225.4 233 1 1 2 2 1 1

9.7 19.7 28.52 479.2 364 152.9 129.8 169.5 187.1 251.6 115.8 112.4 116.4 1 2 2 2 1 1

15.25 38.35 35.1 826.9 320.8 206.7 222.5 222.9 347.7 324.1 159.8 167.7 173.6 1 2 1 1 1 3

9.45 26.46 35.29 860.2 292.7 127 109.7 164.2 259.7 305.7 117.9 83.9 138.9 1 2 1 3

4.84 22.81 29.66 437.7 357.1 80.6 122.7 138.7 250.7 297.5 49.1 74.2 75.1 1 2 2 1 2

26.09 10.51 29.81 707.1 300.5 206.2 216.9 173.8 295.7 335.1 141.1 173.8 184.5 1 2 2 2 1 2

26.32 47.14 54.14 1009.8 597.7 270.8 264 266.8 417 483.3 241.8 234 259.3 1 2 2 2 1 1

17.31 37.07 44.01 993.9 358.1 165.1 181.1 147.3 340 377.8 169 162.3 172.1 1 2 2 2 3 2

17.07 42.05 56.16 398.8 417.7 163.1 223.1 167.8 1 2 2 2 1 2

12.01 32.54 37.96 565.5 301.2 174.2 150.3 203.9 329.9 372.7 124.4 101.8 173.6 1 2 1 2 1 3

22.79 45.82 55.5 956.6 418 180.7 206.5 187.8 394 475.3 177.6 182.7 211 1 2 2 2 1 2

30.11 33.4 41.25 796 515.3 355.9 323 355.9 299.5 426.8 278.9 278.9 284.4 1 1 2 1 2

25.33 33.45 47.7 817.3 449.3 181.6 237 166.1 330.4 437.3 262.1 246.5 255.5 1 1 2 2 1 2

16.33 34.44 44.09 308 388.4 170.1 172.8 171.8 1 2 2 2 1 2

41.51 25.98 40.86 987.8 657.9 496.6 515.7 424.5 243 460.8 294.3 289.5 292.6 1 1 2 1 1