THE DIFFERENTIAL DIAGNOSTICS OF THE MALIGNANT RENAL LESIONS: THE APPLICATION OF THE DIFFUSION- WEIGHTED IMAGING OF THE RENAL CELL CARCINOMA DANYLO HALYTSKY LVIV NATIONAL MEDICAL UNIVERSITY Mytsyk Yulian, M.D., Ph.D., Associate Professor UROLOGY DEPARTMENT | RADIOLOGY DEPARTMENT, LVIV, UKRAINE

Background Renal cell carcinoma (RCC) accounts for about 3% of malignant tumors of the adult population 1. In the oncourology given type of tumors ranks third after prostate and bladder cancer Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA: A Cancer Journal for Clinicians 2009;59(4):225– Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, , National Cancer Institute. Dynamics of morbidity and mortality in patients with RCC in the USA 1 and in Ukraine 2

Among various histological subtypes of RCC clear-cell subtype (ccRCC) is the most common which appears in 80-90% of pathological conclusions 1. 3 Recently, computed tomography (CT) is considered to be the "golden standard" in diagnostic imaging of RCC.

109 renal lesions in 64 patients 4

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Purpose: The objective of the survey was to assess the value of the diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) in differential diagnostics of the malignant renal lesions. 6

Materials and Methods: Study Design 69 persons in total 54 adult patients with RCC confirmed by pathomorphological examination: 25 patients with solid form of ccRCC (I-IV Fuhrman grades) 8 patients with cystic form of the ccRCC (Bosniak type IV ) 12 patients with papillary RCC (pRCC) 9 patients with chromophobe RCC (chRCC) 15 healthy volunteers (the control group) 7 Retrospective study was conducted among

EXCLUSION CRITERIA Patients with renal insufficiency Multifocal RCC Bosniak cysts of I-III classes Metal objects in the body Low image quality and DWI with obvious artifacts 8 In all patients diagnosed with RCC a consecutive partial or radical nephrectomy was performed with subsequent pathological verification of diagnosis. Anti-tumor therapy and biopsy were not performed prior to MRI and surgery.

PATIENTS GROUPS CHARACTERISTICS Group Number of patients SexAge, years MenWomanMean ± SD Solid ccRCC ± 5.2 I Fuhrman grade ± 2.1 II Fuhrman grade ± 3.5 III Fuhrman grade ± 3.9 IV Fuhrman grade ± 4.3 Cystic ccRCC (Bosniak type IV) ± 4.2 Papillary RCC ± 5.1 Chromophobe RCC ± 3.7 Healthy volunteers ± 5.8 9

In all patients and healthy volunteers an MRI was performed, which included DWI, followed by ADC measurement. MR imaging was performed with a 1.5 T body scanner (Signa HDxt, General Electric, USA) using an eight-chan­nel phased-array body coil. Standard GE MRI Protocol included such series: Axial 2D fast imaging employing steady-state acquisi­tion with fat saturation (FIESTA FAT SAT); Axial T1-weighted fast spoiled gradient-recalled echo dual-echo (FSPGR-DE); Axial 3D fat-saturated T1-weighted spoiled gradient echo liver acquisition with volume acquisition (LAVA) with contrast; Axial T2-weighted fast-recovery fast spin-echo (FRFSE); Coronal T2-weighted single-shot fast spin-echo (SSFSE); Sagital T2-weighted SSFSE; 10

DWI parameters Axial DWI was conducted before contrast media administration, using single-shot echo-planar imaging sequence with parallel imaging technique and fat satura­tion during one breath-hold. DWI parameters: TR=12000 ms, TE=90 ms, field of view=40×40 cm; matrix=200×192; NEX=3; bandwidth=250 kHz, dif­fusion direction=slice, slice thickness=6.0 mm, inter­ scan gap=1.0 mm with b-values=0 and 800 mm 2 /s), acquisition time=17 s. 11

Functool software was used for ADC map generation and measurements The region of interest (ROI) was placed within a portion of the area of the lesion where the minimum ADC value on the ADC map was registered according to the color by visual inspection. An average of two to three measure­ments per lesion were performed, depending on the lesion size. The mean ADC value was recorded within ROI. 12 ADC measurement

Statistical Analysis Microsoft Excel 2013 software was used for statistical data analysis. Research was allowed by local Ethics Committee. 13

Results Tumors had predominantly irregular shape on MRI images with irregular and indistinct outlines. 14 Tumor type Number of patients Tumor diameter, cm Mean ± SD Solid ccRCC255.6 ± 2.2 I Fuhrman grade74.8 ± 0.9 II Fuhrman grade56.2 ± 1.1 III Fuhrman grade75.2 ± 0.6 IV Fuhrman grade66.3 ± 0.7 Cystic ccRCC (Bosniak type IV) 67.4 ± 1.9 Papillary RCC126.2 ± 1.2 Chromophobe RCC96.7 ± 2.2

MRI CHARACTERISTICS OF KIDNEY TUMORS 15 Tumor typeMRI features Solid ccRCC Intermediate to high SI on T2 Avidly enhancing Heterogeneous with areas of necrosis Signal loss on opposed-phase relative to in-phase images Cystic ccRCC (Bosniak type IV) Intermediate to high SI on T2 Heterogeneous Containing enhancing soft-tissue components Signal loss on opposed-phase relative to in-phase images Papillary RCC Low SI on T2 Hypoenhancing Signal loss on in-phase relative to opposed-phase images Chromophobe RCCVariable imaging appearance: Low SI on T2 – 62% Intermediate to high SI on T2 – 38% Heterogeneous

16 ABC D Abdominal MRI of a 65-year-old man with pathologically proven ccRCC, Fuhrman grade II. (A) Definite heterogeneous lesion of the anterior part of the right kidney (arrow) on axial FIESTA scan with fat saturation with areas of hyper- and hypointensity; (B) On sagital T2-weighted SSFSE hyperintence lesion of the medium renal segment with well-defined hypointense pseudocapsule (arrows) and central zone; (C) Diffusion-weighted MR, b-value=0 and 800 mm 2 /s, inhomogeneous area with peripheral zone of hyperintesity (arrow); (D) ADC map with hypointense area in the right kidney (left arrow) corresponding to the hyperintese zone on DWI image, ADC=1.84×10 −3 mm 2 /s. The right arrow is pointing on ROI with normal left kidney parenchyma, ADC=2.16×10 −3 mm 2 /s.

17 Abdominal MRI of a 62-year-old woman with pathologically proven ccRCC, Fuhrman grade III. (A) Axial T2-weighted FRFSE, large inhomogeneous lesion of the right kidney with area of hyperintensity in posterior segment (arrow). (B) Diffusion-weighted MR, b-value=0 and 800 s/mm 2, area of defined hyperintesity in the posterior segment of the right kidney (arrows). (C) ADC map with ROI over the hypointense area in the posterior segment of the right kidney (arrow) corresponding to hyperintese zone on DWI image, in given area ADC had the lowest value: 1.79×10 −3 mm 2 /s. A B C

18 ABC D E F MRI of the patient, 68 y.o., pathologically proven chRCC of the left kidney. (A) on sagittal T2-weighted SSFSE large tumor 68×75×55 mm with zones of iso- and hyperintensity and without infiltration into surrounding tissues. (B) on axial T2-weighted FIESTA with fat saturation tumor is presented by regions of iso- and hyperintensity. (E) on axial DWI tumor presented as hyperintense region. (F) ADC-map with b values 0 and 800, ROI1 and ROI2 over the tumor region showed highest ADC values (1.52 × 10 – 3 mm 2 /s and 1.53 × 10 – 3 mm 2 /s) in comparison to ROI3 over the normal renal parenchyma of contralateral kidney (2.15 × 10 – 3 mm 2 /s).

In the result of the performed analysis it was found that the average ADC value of the malignant tumors was significantly different between the histological subtypes of RCC: 19 Group Number of patients ADC value, ×10 −3 mm 2 /s Mean ± SD Solid ccRCC251,81±0.24 I Fuhrman grade71,89±0.18 II Fuhrman grade51,80±0.17 III Fuhrman grade71,74±0.16 IV Fuhrman grade61,70±0.17 Cystic ccRCC (Bosniak type IV)62,08±0.25 Papillary RCC121,61±0.19 Chromophobe RCC91,53±0.21 Healthy volunteers152,18±0.18

20 DIFFERENCE BETWEEN THE HISTOLOGICAL SUBTYPES OF RCC AND NORMAL RENAL PARENCHYMA

21 Comparisons of Renal Lesion ADCs Comparison P Value Solid tumors ccRCC vs pRCC<0.05 ccRCC vs chRCC<0.05 pRCC vs chRCC<0.05 ccRCC grade I vs ccRCC grade II>0.05 ccRCC grade I vs ccRCC grade III>0.05 ccRCC grade I vs ccRCC grade IV<0.05 ccRCC grade II vs ccRCC grade III>0.05 ccRCC grade II vs ccRCC grade IV>0.05 ccRCC grade III vs ccRCC grade IV>0.05 Cystic RCC Cystic ccRCC vs solid ccRCC<0.05 Cystic ccRCC vs pRCC<0.05 Cystic ccRCC vs chRCC<0.05 Cystic ccRCC grades vs each other>0.05

Conclusions We observed a statistically significant difference (P<0.05) in a mean ADC values of solid forms of RCC: ccRCC, pRCC and chRCC - 1,81±0.24×10 −3 mm 2 /s vs 1,61±0.19×10 −3 mm 2 /s vs 1,53±0.21×10 −3 mm 2 /s respectively; The cystic form of ccRCC had significantly higher mean ADC value than the solid forms of RCC - 2,08±0.25×10 −3 mm 2 /s (P<0.05); The method of the diffusion-weighted imaging along with ADC measurement gives valuable information for the differential diagnostics of the malignant renal lesions but have limitations in differentiating between the grades of the solid and cystic forms of ccRCC: statistically reliable difference (P<0.05) was observed only between the ccRCC lesions with I and IV Fuhrman grades of differentiation. 22