Lymph nodes in gynecologic malignancies with imaging biomarkers scope.

Transcription

1 Lymph nodes in gynecologic malignancies with imaging biomarkers scope. Poster No.: C-1291 Congress: ECR 2012 Type: Educational Exhibit Authors: C. Suh, H. J. Choi, M.-H. Kim, K.-S. Cho; Seoul/KR Keywords: Genital / Reproductive system female, Lymph nodes, MRDiffusion/Perfusion, Lymphography, PET-MR, Outcomes analysis, Diagnostic procedure, Staging, Neoplasia DOI: /ecr2012/C-1291 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. Page 1 of 57

2 Learning objectives To understand the imaging of lymph node in gynecologic malignancies with concept of imaging biomarkers. The presence of lymph nodes metastases is the single most important prognostic factor in gynecologic malignancies. Moreover, the presence of nodal metastases is not only alters prognosis but also has a profound effect on treatment planning. Imaging biomarkers refer to anatomic, physiologic, biochemical, or molecular parameters detectable with imaging methods. The use of imaging techniques that have the ability to evaluate tumor biology and function shows a great deal of promise in providing early surrogate biomarkers. In this poster, as imaging biomarkers point of view, the pearls and pitfalls of the currently available and future lymph node imaging modalities will be discussed. All currently available imaging modalities such as US, CT, MR and PET-CT will be discussed. Moreover, evolving techniques will also be reviewed. Page 2 of 57

3 Background Key definitions Biomarker: Objectively measured indicator of biological/pathological process or pharmacologic response to treatment Clinical endpoint (proof of efficacy): Characteristic or variable that reflects patient feeling, function or survival Surrogate endpoint (~cluster): Biomarker intended to substitute for clinical endpoint (predict benefit or harm) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence Fig. 1: Fit-for-purpose biomarkers References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 3 of 57

4 Fig. 5: Biomarkers References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Page 4 of 57

5 Fig. 6: Biomarker modality and clinical endpoint References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Fig. 7: Biomarker modality and pros# References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Page 5 of 57

6 Fig. 8: Imaging biomarker are prededented References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Imaging biomarkers Definition: Anatomic, physiologic, biochemical, or molecular parameters detectable with imaging methods Fig. 2: Imaging biomarkers References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Requirements: Standardization, Information of performance (sensitivity, specificity, reproducibility), Validation against endpoint Page 6 of 57

7 Fig. 3: Imaging biomarkers: Requirements References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Thing to consider for new biomarkers Relation with previous biomarker Incorporated to previous biomarker? Supplemental features? More than TNM stage? What can we add to previous biomarker Stochastic event? Reasonable subgrouping? Page 7 of 57

8 More personalized medicine Biomarkers paradox Fig. 4: Biomakers paradox References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Page 8 of 57

9 Imaging findings OR Procedure details Lymph node Framework - Fibrous capsule - Fibrous trabeculae - Afferent vessels: convex surface - Efferent vessels: concave surface Cortex - Outer, convex portion of LN - B-cell lymphoid follicle Paracortex - Just deep to cortex - T-cell Medulla & hilum - Deep portion of LN - Plasma cell - Artery and vein Lymph node metastasis Metastatic tumors - Most common nonhematopoietic lesion Early involvement site - Subcapsular sinus Micrometastasis - Ø < 2mm LN metastasis(+) in gynecologic malignancy pt referred for surgery: 20% Regional LN status - Major prognostic factor - Decision criteria for adjuvant therapy Selective vs systemic lymphadenectomy - Controversial - Value & optimal extent Page 9 of 57

10 Fig. 9: Lymph node metastasis References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Patterns of Tumor Spread Direct extension - Infiltrating surround tissue - Implantation in serous cavity Lymphatic metastasis Hematogeneous metastasis Page 10 of 57

11 Fig. 10: Patterns of Tumor Spread 1: 1-5%, 2: 15-30%, 3: 30%, 4: 50% References: Bast RC, et al. Cancer Medicine, 5th ed, 454, 2000 <Cervical Cancer> Introduction Cervical cancer - Second most common malignancy in women - Clinically staged (FIGO): 60% accuracy Ballon SC et al. Obstet Gynecol 1981; 57:90-95 LN metastasis - Not included in FIGO - Closely associated with prognosis No LN meta: 57% 5-year survival Pelvic LN meta: 34% 5-year survival Paraaortic LN meta: 12% 5-year survival Lanciano RM et al. Semin Radiat Oncol. 1994; 4:46-5 Staging I : confined to cervix II : extension beyond cervix, spare pelvic wall III : lower 1/3 vagina, pelvic wall IV : extension beyond pelvic cavity, adjacent organ Lymphatic Spread Route Primary LN: parametrial LN, obturator LN, internal iliac LN, external iliac LN, sacral LN Secondary LN: common iliac LN, inguinal LN, paraaortic LN Supraclavicular LN - Left predominent Page 11 of 57

12 - 5% - Up to 35%: Paraaortic LN (+), common iliac LN(+) - Dismal prognosis: 10-17mo survival Fig. 12: Lymphatic Spread Route: Supraclavicular LN References: Tran BN, et al. Gyn Oncon 2003;90: Sentinel Lymph Node Definition - First LN in the lymphatic area into which primary tumor drains Hypothesis - Status of sentinel lymph node (SNL) reflect lymphatic area - SNL(-) -> LNs in lymphatic area (-) Page 12 of 57

13 - SNL(+) -> LNs in lymphatic area (+) Tumors using SNL - Melanoma, breast cancer - Cervical cancer, vulva cancer Markers - Dyeing agent: Isosulfan blue, patent blue V, methylene blue - Radioactive substance: Technetium-99 radioisotope Pathologic tech - Multisection, immunohistochemical analysis Lymph Node Metastasis in cervical cancer Fig. 13: LN metastasis in cervical cancer References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR LN metastasis - Nodal resection before RT: improved survival Downey GO et al. Am J Obstet Gynecol. 1989; Inaccurate LN assessment: suboptimal treatment Imaging modality accuracy & sensitivity - MRI: % & 24-89% - PET: % & 38-99% - PET/CT: 85-72% & 58-72% Imaging Criteria of LN metastasis: MRI Short axis Ø 1cm - Round Ø 0.8cm, ovoid Ø 1cm - More than 3 LNs (0.5 cm# Ø 1cm) Margin: lobulated or spiculated Necrotic portion Heterogeneous enhancement Page 13 of 57

14 Fatty hilum (-) Imaging sequence - T2WI: Internal signal intensity -ddx from muscle and vessel - Postcontrast: Enhancement, necrosis - Diffusion WI: Signal intensity change with microstructure of LN Lymphotropic superparamagnetic nanoparticles: T2*W gradient echo Fig. 14: Cervical cancer LN in MRI References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR LN detection by MRI - Harvested LNs : MR detected LNs : 86 - MR detection rate : 4.5% Diameter of LNs (p=0.049) - Metastatic LNs : 9.3 mm - Nonmetastatic LNs : 7.5 mm Page 14 of 57

15 Fig. 15: Choi HJ, et al. AJR 2006 References: Choi HJ, et al. AJR 2006 Helpful findings - Lobulated or spiculated border (p=0.044) Desmoplastic reaction or tumor infiltration 6 of 12 metatatic LNs (Ø<9mm) additionally detected - Heterogeneous enhancement (p=0.076) Useful findings in H&N cancer Som PM et al. AJR 1992;158: Van den Brekel et al. JCAT 1990;14: Tumor infiltration, necrosis, mucin pool Major problem - Enlarged reactive LN - Small LN (#1cm) 37% of metastatic LN: micrometastasis (#2mm) Giradi F et al. Gyn Oncol 1993;49: % of metastatic LN: small LN (#1cm) Ayhan A et al. Eur J Obstet Gyn 1995;60:61-3 MRI, USPIO (ultrasmall superparamagnetic iron oxide contrast agent) Page 15 of 57

16 Fig. 16: MRI, USPIO References: Harisinghani MG, Barentsz JO, et al NEJM 2003;25: Fig. 17: MRI, USPIO References: Rockall AG, et al JCO 2005;20 PET Page 16 of 57

17 Fig. 18: PET References: Chou HH, et al. Journal of Clinical Oncology 2006 Fig. 19: PET References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Page 17 of 57

18 Fig. 20: PET References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR MRI Fig. 21: MRI Page 18 of 57

19 References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Fig. 22: MRI References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR PET-CT Principal - Mechanically combined PET and CT - More accurate alignment in focused scan - Up to 250 block of detecting ring Limitation of PET - Spatial resolution# - Physiologic uptake - Anatomical detail# PET/CT - Spatial resolution# - Equivocal interpretation# PET/CT vs PET in non-small cell lung ca LN metastases - Accuracy: 96% versus 93% (p = 0.01) Cerfolio et al. Ann Thoracic Surg. 2004; Page 19 of 57

20 Fig. 23: PET-CT References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Patients - 22 untreated patients with FIGO IB-IVA - October 2003-January Age: (mean; 50yrs) - No contraindication to surgery - No evidence of distant metastasis - Patients not to undergo PET/CT (n=63) and small cell carcinoma (n=2) excluded Fig. 24: Region Specific Comparison Accuracy: standard power 0.26, 685 nodal group needed (alpha 0.05,power 0.80) References: Choi HJ, et al. Cancer 2006 Page 20 of 57

21 Fig. 25: Patient-by-patient comparison Accuracy: standard power 0.75, 98 patients needed (alpha 0.05,power 0.80) References: Choi HJ, et al. Cancer 2006 MRI (region specific comparison) - Sensitivity: 24.2% - Specificity: 97.4% - Accuracy: 91.4% Choi HJ et al. Am J Roentgenol PET (region specific comparison) - Sensitivity 38% - Specificity 97% - Accuracy 93% Park SY et al. Eur J Cancer 2005 Terahertz Imaging as an imaging biomarkers Page 21 of 57

22 Fig. 26: Terahertz Imaging Rabbit Tm References: Park JH, Choi HJ, Son JH et al. APL 2011 Fig. 27: Terahertz Imaging LN Page 22 of 57

23 References: Jung E, Choi HJ, Han HW et al. JOSK Accepted Fig. 28: In vitro Feridex transfected SKOV3 cell imaging. A, Gross imaging, B, MR T2*, and C, THz images of SKoV3 cancer cells transfected by different Feridex concentrations 0, 0.35, 0.7, 1.38 mm. Note gradual decrease in MR signal and increase in reflection in THz imaging with increasing Feridex concentration. References: Park JH, Choi HJ, Son JH et al. IEEE TST submitted Page 23 of 57

24 Fig. 29: In vivo imaging. A, Tumor is well delineated in THz imaging and in MR image. B, THz signal responsibility of cancerous cell site and normal cell site. References: Park JH, Choi HJ, Son JH et al. IEEE TST submitted Status - Exploration or demonstration Pros - Non ionizing (not hazardous for human) - Tissue characterizations - Still new (more fund!!) - Surface image (added value!) Cons - Surface image (no tomography!) - Long acquisition time - Small field of view - No definite added view - No contrast agent <Ovarian Cancer> Staging I : confined to ovary II : Uterine appendage, pelvic wall, pelvic organ Page 24 of 57

25 III : Extension to abdominal cavity, LN metastasis IV : Distant metastasis Fig. 30: Ovarian cancer staging. References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Lymphatic Spread: Different patterns with stage Early stage: ipsilateral primary lymphatic group Advanced stage: several lymphatic group Benedetti-Panici P et al. Gynecol Oncol 1993;51:150-4 Independent of anatomy of lymphatic drainage - 33% pelvic chain - 8% paraaortic chain - 80% pelvic + paraaortic chain Musumeci R et al. AJR 1980 Page 25 of 57

26 Fig. 31: Ovarian cancer LN metastasis I-IV. References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 26 of 57

27 Fig. 32: Ovarian cancer LN metastasis I-IV. References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Fig. 33: Staging of Advanced Ovarian Cancer: Comparison of Imaging ModalitiesReport from the Radiological Diagnostic Oncology Group References: Tempany CMC, et al. Radiology 2000 Less Attention for LN Metastasis Surgical staging No main route of transmission Page 27 of 57

28 Systemic removal of LNs - Controversial Fig. 34: Systematic Aortic and Pelvic Lymphadenectomy Versus Resection of Bulky Nodes Only in Optimally Debulked Advanced Ovarian Cancer: A Randomized Clinical Trial. References: Panici PB, et al. Journal of the National Cancer Institute 2005 <Endometrial Cancer> Staging I : confined to endometrium, myometrium II : extension to cervix III : uterine appendage, abdominal organ, LN meta IV : mucosa of rectum or bladder, distant meta Page 28 of 57

29 Fig. 36: Endometrial cancer staging References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 29 of 57

30 Fig. 35: Endometrial cancer LN metastasis I-IV. References: RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER Seoul/KR Less Attention for LN Metastasis Surgical staging No main route of transmission Systemic removal of LNs - Controversial Page 30 of 57

31 Images for this section: Fig. 2: Imaging biomarkers RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 31 of 57

32 Fig. 4: Biomakers paradox RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Fig. 1: Fit-for-purpose biomarkers RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 32 of 57

33 Fig. 5: Biomarkers RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 33 of 57

34 Fig. 6: Biomarker modality and clinical endpoint RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Fig. 7: Biomarker modality and pros# RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 34 of 57

35 Fig. 8: Imaging biomarker are prededented RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 35 of 57

36 Fig. 9: Lymph node metastasis RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 36 of 57

37 Fig. 10: Patterns of Tumor Spread 1: 1-5%, 2: 15-30%, 3: 30%, 4: 50% Bast RC, et al. Cancer Medicine, 5th ed, 454, 2000 Page 37 of 57

38 Fig. 11: Lymphatic Spread Route Harpreet K, et al. Radiographics 2001;21: Page 38 of 57

39 Fig. 12: Lymphatic Spread Route: Supraclavicular LN Tran BN, et al. Gyn Oncon 2003;90: Page 39 of 57

40 Fig. 13: LN metastasis in cervical cancer RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Fig. 14: Cervical cancer LN in MRI RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 40 of 57

41 Fig. 15: Choi HJ, et al. AJR 2006 Choi HJ, et al. AJR 2006 Fig. 16: MRI, USPIO Harisinghani MG, Barentsz JO, et al NEJM 2003;25: Page 41 of 57

42 Fig. 17: MRI, USPIO Rockall AG, et al JCO 2005;20 Fig. 18: PET Chou HH, et al. Journal of Clinical Oncology 2006 Page 42 of 57

43 Fig. 19: PET RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Fig. 20: PET RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 43 of 57

44 Fig. 21: MRI RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Fig. 22: MRI RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 44 of 57

45 Fig. 23: PET-CT RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Fig. 24: Region Specific Comparison Accuracy: standard power 0.26, 685 nodal group needed (alpha 0.05,power 0.80) Choi HJ, et al. Cancer 2006 Page 45 of 57

46 Fig. 25: Patient-by-patient comparison Accuracy: standard power 0.75, 98 patients needed (alpha 0.05,power 0.80) Choi HJ, et al. Cancer 2006 Fig. 27: Terahertz Imaging LN Jung E, Choi HJ, Han HW et al. JOSK Accepted Page 46 of 57

47 Fig. 28: In vitro Feridex transfected SKOV3 cell imaging. A, Gross imaging, B, MR T2*, and C, THz images of SKoV3 cancer cells transfected by different Feridex concentrations 0, 0.35, 0.7, 1.38 mm. Note gradual decrease in MR signal and increase in reflection in THz imaging with increasing Feridex concentration. Park JH, Choi HJ, Son JH et al. IEEE TST submitted Page 47 of 57

48 Fig. 29: In vivo imaging. A, Tumor is well delineated in THz imaging and in MR image. B, THz signal responsibility of cancerous cell site and normal cell site. Park JH, Choi HJ, Son JH et al. IEEE TST submitted Fig. 26: Terahertz Imaging Rabbit Tm Page 48 of 57

49 Park JH, Choi HJ, Son JH et al. APL 2011 Fig. 30: Ovarian cancer staging. RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 49 of 57

50 Fig. 31: Ovarian cancer LN metastasis I-IV. RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 50 of 57

51 Fig. 32: Ovarian cancer LN metastasis I-IV. RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Fig. 33: Staging of Advanced Ovarian Cancer: Comparison of Imaging Modalities-Report from the Radiological Diagnostic Oncology Group Tempany CMC, et al. Radiology 2000 Page 51 of 57

52 Fig. 34: Systematic Aortic and Pelvic Lymphadenectomy Versus Resection of Bulky Nodes Only in Optimally Debulked Advanced Ovarian Cancer: A Randomized Clinical Trial. Panici PB, et al. Journal of the National Cancer Institute 2005 Page 52 of 57

53 Fig. 35: Endometrial cancer LN metastasis I-IV. RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 53 of 57

54 Fig. 36: Endometrial cancer staging RADIOLOGY, ASAN MEDICAL CENTER, ASAN MEDICAL CENTER - Seoul/KR Page 54 of 57

55 Conclusion The CT and MR remains the cornerstone in nodal assessment in gynecologic malignancies. But known diagnostic performances of CT and MRI are low to replace surgical staging. Recently, MR lymphography with iron oxide nanoparticles and MR DWI are explored and more researches have been performed. But, researches for these studies remain in the early stage and more validation with multicenter scale is needed to be a surrogate biomarker. With ongoing technological advances, novel imaging techniques will have significant potential to provide new biomarkers of metastatic lymph node which will ultimately impact on cancer management. Page 55 of 57

56 Personal Information Page 56 of 57

57 References 1. Choi HJ, Kim SH, Seo SS, et al. MRI for Pretreatment Lymph Node Staging in Uterine Cervical Cancer. AJR 2006;187:W Rochall AG, Sohaib SA, Harisinghani MG, et al. Diagnostic Performance of Nanoparticle-Enhanced Magnetic Resonance Imaging in the Diagnosis of Lymph Node Metastases in Patients With Endometrial and Cervical Cancer. JCO 2005;23: Chou HH, Chang TC, Yen TC, et al. Low Value of [18F]-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Primary Staging of Early-Stage Cervical Cancer Before Radical Hysterectomy. JCO 2006;24: Choi HJ, Roh JW, Seo SS, et al. Comparison of the Accuracy of Magnetic Resonance Imaging and Positron Emission Tomography/Computed Tomography in the Presurgical Detection of Lymph Node Metastases in Patients with Uterine Cervical Carcinoma A Prospective Study. Cnacer 2006;106: Tempany CM, Zou KH, Silverman SG, et al. Staging of advanced ovarian cancer: comparison of imaging modalities--report from the Radiological Diagnostic Oncology Group. Radiology. 2000;215(3): Page 57 of 57