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IMAGING OF NON SMALL CELL LUNG CARCINOMA

NSCLC: FROM MORPHOLOGY TO

FUNCTIONAL IMAGING

Dr. Yeung Wing Hang, Calvin Specialist in Radiology

Hong Kong Baptist Hospital

MEDICAL IMAGING

•  80s anatomical imaging: XR,CT,US •  90s anatomical imaging: CT,MR,US,DR •  00s functional imaging: DSCT, PET-CT,

MR •  NEXT: ?

MEDICAL IMAGING

•  80s anatomical imaging: XR,CT,US •  90s anatomical imaging: CT,MR,US,DR •  00s functional imaging: DSCT, PET-CT,

MR •  NEXT: ?

MULTIDETECTOR CT (MDCT)

1971 First head CT scanner 1974 Body CT scanner 1989 Spiral/ helical CT scanner 1998 Multidetector CT (4 slices) 2001/2 Multidetector CT (16) RECENT 64,128,320,DSCT……

LN

7

10 11-14

4L 4R

10

LN

3P

4R

3A

4L 5

Mediastinal invasion

T4

Vertebral invasion

T4

Adrenal metastases

M1b

Adenocarcinoma

Adenocarcinoma

NSCLC T2b (6cm)

Adenocarcinoma in situ

Adenocarcinoma in situ

Adenocarcinoma

Adenocarcinoma

Adenocarcinoma

Adenocarcinoma

MEDICAL IMAGING

•  80s anatomical imaging: XR,CT,US •  90s anatomical imaging: CT,MR,US,DR •  00s functional imaging: DSCT, PET-CT,

MR •  NEXT: ?

FUNCTIONAL IMAGING

•  DUAL ENERGY CT IMAGING •  DIFFUSION WEIGHTED IMAGING •  PET-CT IMAGING •  PET-MR IMAGING

DUAL ENERGY CT (DECT) IMAGING

• material differentiation, identification and quantification

•  iodinated attenuation maps • monochromatic images • virtual unenhanced images

DUAL ENERGY CT (DECT) IMAGING

• clear advantages in tumor detection, lesion characterization, and evaluation of response to therapy

DUAL ENERGY CT (DECT) IMAGING

•  in the detection of oncology-related disorders (e.g., pulmonary embolism and bowel ischemia) and comorbidities (e.g., renal stones and gout)

DUAL ENERGY CT (DECT) IMAGING

• application of two distinct energy settings •  to differentiate materials with different

molecular compositions on the basis of their attenuation profiles

•  result in a transition from attenuation based imaging to material-specific or spectral imaging

Dual Energy (Spectral) Imaging Can differentiate & classify tissue composition

DECT IMAGING IN NSCLC

•   iodine maps for assessment of the relative vascularity of pulmonary nodules

•  tissue enhancement can be accurately assessed on iodine maps

DECT IMAGING IN NSCLC

•   on virtual unenhanced images, a reduction in the size of calcifications compared with that in actual unenhanced datasets

•  there is a risk of overlooking small calcified lesions

DECT IMAGING IN NSCLC

• To the differentiation of calcification from enhancing tissue in solitary pulmonary nodules is made with a single contrast-enhanced CT acquisition and virtual nonenhanced image reconstruction

DECT IMAGING IN NSCLC

• DECT  could  serve  as  a  valuable  func3onal  imaging  test  for  pa3ents  with  NSCLC  as  iodine  related  a>enua3on  correlates  with  SUV  of  FDG  PET-­‐CT      

(Schmid-­‐Bindert  G  et  al,  Eur  Radiol  2012)  

Adenocarcinoma

Adenocarcinoma

Adenocarcinoma

Water Image (VNC)

Iodine Image

Non Small Cell Lung CA

Water Image (VNC)

Iodine Image

DECT EVALUATION OF RESPONSE TO THERAPY

•   accurately assess the intratumoral amount of iodinated contrast medium to represent the perfusion and vascularization of lesion

•  the iodine map is more robust parameter than attenuation (not influenced by intratumoral hemorrhage)

DISORDERS RELATED TO ONCOLOGIC THERAPY

•   pulmonary thromboembolism •  bowel ischemia •  comorbidities in oncologic patients:

renal stones and gout

Gout (Uric Acid Deposit)

Diffusion weighted image of NSCLC

• DWI is sensitive to the random (Brownian) motion of water molecules. In biologic tissue, the presence of impeding barriers (e.g., cell membranes, fibers, and macromolecules) interferes with the free displacement (diffusion) of water

• The signal intensity in DWI depends on the separation and permeability of these impeding boundaries

)

Relationship between change in tissue cellularity and water mobility

Restricted Diffusion: highly cellular environment, water diffusion is restricted because of reduced extracellular space and impermeability of cell membrane. (eg. Solid tumour/ malignancy) Result: Low ADC value

Free Diffusion: Increase in extracellular space and membrane permeability allow greater water mobility (eg water/ necrosis/ benign lesions) Result: High ADC value ADC: Apparent Diffusion Coefficient

DIFFUSION WEIGHTED IMAGE (DWI)

•  differentiation between benign and malignant tumour

•  decreased Brownian motion of water in malignant tumour (increase cellularity)

•  non-contrast, no ionizing radiation, fast

DIFFUSION WEIGHTED IMAGE (DWI)

• ADC has been correlated with important histologic properties, including the tumor proliferation index, tumor grade, the presence of necrosis, and tumor cell apoptosis

• ADC is highly reproducible

DIFFUSION WEIGHTED IMAGE (DWI)

DWI ADC

HIGH LOW Tumor, rarely abscess, viscous fluid, blood product

HIGH HIGH T2 shine through, liquefactive necrosis

LOW HIGH Fluid

LOW LOW Fat, susceptibility arfefacts

DIFFUSION WEIGHTED IMAGE (DWI)

False-positive findings: •  artifacts from image ghosting, poor fat

suppression, or susceptibility effects. The clue to artifacts is that they may appear as recapitulation of structures seen elsewhere on the image or appear at boundaries between fat and water interfaces

DIFFUSION WEIGHTED IMAGE (DWI)

•   normal lymph nodes •  tiny foci (typically 1–2 mm) of impeded

diffusion are sometimes detected that are difficult to correlate with structures, ? small venules

DIFFUSION WEIGHTED IMAGE (DWI)

False-negative findings: •  normal structures can exhibit impeded

water diffusion, e.g. salivary glands, lymph nodes, spleen, spinal cord, ovaries, testes, red marrow, endometrial lining, bowel wall, peripheral nerves, and neural ganglia

• some of the well differentiated adenocarcinoma

Diffusion weighted image of NSCLC

• Pathologic processes that alter the physical nature of the restricting barriers in biologic tissue affect the diffusivity of the water molecules, which can be visualized and quantified using DWI

• A known clinical application is diagnosis of acute ischaemic stroke

Diffusion weighted image of NSCLC

•  Important technologic advances, including echoplanar imaging, high-gradient amplitudes, multichannel coils, and parallel imaging, have extended the applications of DWI outside the brain

• Limitation of DWI in the thorax has been overcome by the demonstrated feasibility of DWI under free breathing (the concept of diffusion-weighted whole-body imaging with background body signal suppression)

Diffusion weighted image of NSCLC

• Diffusion in biologic tissue is quantified by means of an apparent diffusion coefficient (ADC)

• At least 2 images with 2 different b-values have to be acquired to calculate an ADC

Diffusion weighted image of NSCLC

• Lesion–to–spinal cord ratio (LSR) was introduced, which is a semiquantitative measure that represents the ratio of lesion signal intensity to spinal cord signal intensity

• LSR takes into account both diffusion and T2 relaxation time, does not suffer from image misregistration

Diffusion weighted image of NSCLC

• Kanauchi et al. : nodules with low signal intensity on DWI, comparable to or even lower than that of the spinal cord (i.e., LSR ≥ 1), were classified as positive on DWI. Otherwise, they were considered negative on DWI

• The SUVmax of DWI-positive patients (10.33 ± 4.93) was significantly higher (P < 0.001) than that of DWI-negative patients (3.10 ± 4.21)

Adenocarcinoma

NSCLC

WB Diffusion Stage IV Lung CA (lung, liver, LN, bone)

Pul. Mets. Liver & Spine Mets.

RadioGraphics November-December 2011 vol. 31 no. 72059-2091

55/F NSCLC STAGE 4

ADC:  1.01  x  103mm2/s   ADC:  1.24  x  103mm2/s   ADC:  2.15  x  103mm2/s  

21/10/2009   5/11/2009   23/11/2009  

DIFFUSION WEIGHTED IMAGE (DWI)

• Diffusion-weighted MR imaging might be useful for monitoring the early response to and the prognosis after chemotherapy of NSCLC

• Patients with advanced NSCLC might be able to avoid the cost of and cytotoxic damage from ineffective drugs and might be able to switch anticancer drugs early if drugs were deemed ineffective on the basis of early ADC change

(Yabuuchi  et  al)    

3/6/2011 11/5/2012

55/F Hx of CA lung, post lobectomy

PET

11/5/2012

3/6/2011

MR Whole Body Diffusion

Normal 40/M treated NPC with Lung Liver & Bone Mets

Functional MR Imaging without Contrast

66/M Lymphoma

TUMOURS

•    independence from growth signals •  insensitivity to growth-inhibitory signals •  evasion of apoptosis •  development of a limitless potential for

replication •  development of sustained

angiogenesis •  tissue invasion and metastasis

CT/PET

Improve on the ability of the state of art CT to:

•  detect tumour •  define the extent of tumour •  measure response to treatment

CT/PET

• FDG is not a target-specific PET tracer • studies have shown that an SUV of 2.5 as the

cutoff value will detect malignancy at sensitivity of 97% and specificity of 78%.

CT/PET

• a considerable reduction in SUV was associated with a pathologic response and proved to be a better predictor of long-term survival than anatomy-based criteria in patients with NSCLC who underwent neoadjuvant therapy, followed by complete resection

CT/PET

• a decrease in SUV >20% after one cycle of chemotherapy was associated with a longer time to progression and a longer median overall survival time in stage IIIB or IV NSCLC

• significantly  longer  median  survival  3me  was  found  in  pa3ents  with  complete  metabolic  response  than  in  pa3ents  with  incomplete  metabolic  response  in  stage  IIIA-­‐N2  disease    

CT/PET

• a larger decrease in SUV was observed in responding patients than in nonresponders on CT imaging

• volumetric PET parameters could provide meaningful information about patient prognosis

• PERCIST (Positron Emission Tomography Response Criteria in Solid Tumors)

CT/PET

• FDG is not a target-specific PET tracer • emerging new PET radiotracers may offer a clear

opportunity to improve the study of many biologic features

• Fluoride-18-fluorothymidine (FLT) is used for the noninvasive measurement of tumor proliferation

• Cu(II)-diacetyl-bis(N4)-methylthiosemi- carbazone (Cu-ATSM) for hypoxia

CT/PET

• 18F-FLT uptake is specific for malignant lesions and that there was a significant correlation between 18F-FLT uptake and proliferative activity

• 18F-FLT PET imaging may have a potential role in the evaluation of response assessment in lung cancer, particularly when the treatment approach includes inhibitors of proliferative activity such as cyclin-dependent kinase inhibitors

MR/PET

Advantages over PET/ CT: •  the superior soft tissue contrast of MRI

allows better anatomical visualization of soft tissue structures and bone marrow than CT.

•  simultaneous image acquisition enables temporal co-registration of dynamic PET data acquisition and morphologic/functional MR data. MR perfusion, fMRI, DWI

MR/PET

Advantages over PET/ CT: •  some studies comparing whole-body MR

with PET/CT have shown potential advantages of MR particularly regarding the early detection of brain-, liver- and bone marrow metastases

•  in fully integrated systems, MRI could also be used to provide a gating signal in addition to imaging

MR/PET • PET/MR demonstrated higher sensitivity

than PET/CT for all pulmonary nodules at 61.6 % and 70.3 %

• PET/MR delivered greater sensitivity than PET/CT in the detection of FDG-avid nodules at 94.4 % and 95.6 %

• sensitivity for small non-FDG-avid nodules was lower with PET/MR imaging than with PET/CT

(Hersh Chandarana et al)

MR/PET

•   Contraindications of MR scan, eg. most types of cardiac pacemakers and implanted defibrillators as well as certain metallic implants

NEW DRUGS

•  target the EGFR pathway in NSCLC, small-molecule inhibitors of the tyrosine kinase domain of EGFR were developed (erlotinib and gefitinib)

• activating EGFR mutations were discovered in cancer cells from patients with NSCLC who responded to the targeted therapy with gefitinib and erlotinib

NEW DRUGS

• EGFR mutations in lung adenoCA are seen in approximately in 15% of patients in the United States and in 30% to 50% of patients in Asia

• clinical features are known to be associated with both EGFR mutations and response to gefitinib and erlotinib, including nonsmoker status, Asian ethnicity, and female gender

NEW DRUGS

•     morphological assessment, RECIST uses unidimensional measurements of the sum of the longest lesion diameters

•  many targeted agents are cytostatic and therefore tumor shrinkage may not be seen

NEW DRUGS

•    functional imaging techniques, such as perfusion CT, dynamic susceptibility contrast MR imaging, dynamic contrast-enhanced (DCE) MR imaging, or diffusion-weighted MR imaging, provide information on tissue phenotype or behavior

NEW DRUGS

Comparison of Cytotoxic Therapy versus NODs • Tumoral effect: Cytotoxic Vs cytostatic • Criteria for tumor response: Tumor

shrinkage Vs Tumor stabilization or shrinkage

•  Imaging techniques for response evaluation: Anatomic (size and appearance) Vs functional or molecular imaging

NEW DRUGS

Comparison of Cytotoxic Therapy versus NODs • Time of response evaluation: Late (2 mo)

Vs Early (2–6 wk) • Toxic effects of drugs Usually nonspecific:

multisystemic involvement Vs Less toxic: target-specific toxic effects

RadioGraphics November-December 2011 vol. 31 no. 72059-2091

MEDICAL IMAGING

•  80s anatomical imaging: XR,CT,US •  90s anatomical imaging: CT,MR,US,DR •  00s functional imaging: DSCT, PET-CT,

MR •  NEXT: MOLECULAR IMAGING

MOLECLAR IMAGING • Molecular  imaging  is  expected  to  have  a  major  impact  on  the  early  diagnosis  of  diseases  and  disease  monitoring  in  the  next  decade  

• Nuclear  imaging  techniques  have  been  the  mainstay  of  molecular  imaging  in  the  clinical  arena  

• Con3nued  development  of  molecularly  targeted  contrast  agents  for  nonnuclear  imaging  techniques  such  as  MR,  CT  and  US

MOLECULAR IMAGING

CONCLUSION

Along with molecular metabolic mechanisms of tumor cells that increasingly come to light, rapid development of functional and molecular imaging has taken place in recent years. By directly visualizing and measuring the biological process in vivo, functional and molecular imaging enables early assessment of response to anticancer treatment for NSCLC patient

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