Critical meta-analysis of the diagnostic criteria employed for the sonography (US) diagnosis of lymph node metastasis in the melanoma patient

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1 Critical meta-analysis of the diagnostic criteria employed for the sonography (US) diagnosis of lymph node metastasis in the melanoma patient Poster No.: C-0992 Congress: ECR 2011 Type: Scientific Exhibit Authors: O. Catalano, A. Nunziata, F. Sandomenico, S. V. Setola, A Gallipoli D'Errico ; Naples/IT, Ercolano/IT, Napoli/IT Keywords: Lymph nodes, Oncology, Ultrasound, Diagnostic procedure, Metastases DOI: /ecr2011/C-0992 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 23

2 Purpose Cutaneous melanoma is a frequent disease, especially in some geographical area, and its incidence has significantly increased worldwide in the last years. Key points for disease staging a prognosis include primary tumor thickness, primary tumor ulceration, primary tumor mitotic rate, number of affected lymph nodes, and nodal metastatic burden. 1,2 Approximately 70% of all melanoma metastases involve the regional lymphatic basin, where the first draining lymph node is called the sentinel lymph node and is the basis for treatment planning: if the sentinel lymph node is positive the patient undergoes completion lymphadenectomy while in the sentinel lymph node is negative radical lymphadenectomy will be avoided. Both satellite (< 2 cm) and in-transit (> 2 cm) metastasis may develop along the route of spread from the primary tumor and the lymph 1,2 node; these tumor deposits are comprised in the "N" parameter (Fig.1 on page 3). Establishing the lymph node status is fundamental for initial patient staging, therapeutic 2 management, follow-up, and prognosis. The "N" status is the best predictor for overall survival, which is significantly greater if only one lymph node is found involved and if the diameter of this node is <15 mm. 2,3 3,4 Although the effective impact of sonography (US) on patient survival is still debated, this imaging modality has consistently entered the clinical practice of melanoma, 5-8 particularly in Europe and Australia. US is being increasingly employed in the staging of melanoma patients scheduled for the sentinel lymph node biopsy (SLNB) procedure: in this subjects US is carried out in a non-targeted way, exploring all regional lymphatic stations, or in a targeted way, evaluating specifically those lymph node found "hot" at the pre-slnb lymphoscintigraphy. 2,7,9 The complex and expensive SLNB procedure can be 5,6,10 avoided in US positive cases, which are directly driven to radical lymphadenectomy. Additionally, US is employed during patient follow-up, having it proven more accurate 3,8 than physical examination in detecting locoregional relapse Both during treatment planning and follow-up, US is also relevant to guide percutaneous procedures such as 5,6,10 fine-needle aspiration cytology (FNAC) sampling and surgical guidewire placement. The literature on US imaging of melanoma regional spread has some peculiarity. First, the published papers are mainly written by dermatologists and are mostly focused on the clinical impact of US (management, prognosis, etc.), will little attention is given to the proper use of the US technique for itself. The equipment and the exploration methodology are usually described in a concise manner, making it difficult to full understand the imaging technique employed. Most papers rely on the B-mode imaging without any help from Doppler techniques. The diagnostic criteria considered for lymph node metastasis are frequently vague, without clear and univocally-stated definitions. Some papers simply Page 2 of 23

3 do not indicate the diagnostic criteria employed 8-10 while some others. 3,11 generically 12 state to have employed "modified" criteria from those originally developed by Vassallo. In some papers it is unclear if each single criterion described was considered as a standalone indicator of malignancy or if a combination of different criteria was necessary Moreover, it is uncommon that the accuracy of each single diagnostic criterion is evaluated statistically. Finally, the terminology employed is extremely variable and somehow unusual. We carried out a systematic review of the original articles dealing with US imaging of lymph node melanoma metastasis. Our main interest was focused on the criteria employed in the literature to diagnose nodal metastasis. Images for this section: Fig. 1: Fig.1 - N staging parameter (from Edge SE et al (eds): AJCC Cancer Staging Manual. New York, Springer, 2009). Page 3 of 23

4 Methods and Materials The study was approved by the Ethics on Research Committee of our institution. We employed a multimodal search strategy, focused on the online bibliographical database PubMed, personal files, and consultation with experts. On PubMed we checked the last thirty years, ending December We searched jointly for the terms [melanoma, sonography, lymph node] and for the terms [melanoma, ultrasound, lymph node]. The references of the studies that fulfilled the inclusion criteria were also analyzed to identify original studies that were not identified by the search of the data. Inclusion criteria were: exclusive relationship to melanoma metastasis (exclusion of papers also including other primary tumors) availability of full text, and use of the English language. Papers dealing with non-cutaneous primary melanomas and with deep lymphadenopaties were excluded as well studies on animals. Abstracts and case reports were also excluded. Review articles and editorials were taken in consideration only if they categorized the criteria for nodal metastasis diagnosis (instead, no original data on US methodology and US accuracy is usually included in this kind of papers). The Pubmed search identified 148 papers for the key words "melanoma - sonography lymph node" and 190 papers for the key words "melanoma - ultrasound - lymph node". Among the cumulative 201 papers, 147 were found as not being properly related to the topic of US imaging of melanoma lymphadenopaties or as being written in non-english languages. This first selection left 54 papers for further assessment and their full text versions were collect. No paper was excluded because of our inability to get the full text. Data were extracted from these 54 studies, although 23 were subsequently excluded because of having no specific relevance. No overtly duplicated paper was found, although some articles, written by the same groups, surely had a number of shared patients. In the end, complete information could be extracted from a total of 31 final eligible studies. Screening of the references cited in the retrieved articles failed to identify any additional eligible paper. Images for this section: Page 4 of 23

5 Fig. 1: Fig.19 - Partial lymph-node metastasis. Hypoechoic, hypervascularized tumor deposit in an inguinal lymph node. Page 5 of 23

6 Results The data retrieved from the studies we selected on the topic of US scanning for lymph node melanoma metastasis are listed in table 1 on page 7. The diagnostic criteria described in these papers are shown in table 2 on page. On the basis of this critical review we summarize below some consideration on the assessment of lymph nodes in the melanoma patient. First of all, the operator should be adequately aware of the US appearance of normal, reactively-enlarged, involutively-enlarged (fatty metamorphosis), inflammatory (acute and chronic lymphadenitis), and neoplastic lymph nodes (Fig.2 on page 9, Fig.3 on page 9, Fig.4 on page 10, Fig.5 on page 11). He/she should also be aware that the appearance of normal lymph nodes may differ between the various lymphatic stations (neck, axilla, and inguinal region). To assess the abnormal lymph nodes, combination of B-mode and color-doppler pattern should be considered (Fig.6 on page 12, Fig.7 on page ). Lymph node assessment is based on analyzing the size, shape, border, and internal echotexture. We do not rely on the lymph node size by itself (Fig.8 on page ). 21,24 2 Some older papers consider a longitudinal diameter >2 cm or >3 cm as a suspicion criterion. We do not, but we believe that a lymph node with a non-specific appearance becomes more suspicious when it also shows a large size. Small-sized lymph nodes may sometime appear as round or may show a loss of the hilum hyperechogenicity or a cortical thickening but they will still be regarded as benign if these changes are not so marked. Instead, the same changes would be considered suspicious in a large size lymph node. We take in consideration the shape of the lymph node, being suspicious when oval or even more when round and being not suspicious if markedly elongated (Fig.9 on page, Fig.10 on page ). Some author consider as suspect a longitudinal/ 21,30,36,41 transverse (L/T) diameter <2 12,14,19 <1.5. while some other author, as well as us, an L/T ratio We believe that a 1.5 threshold increases the rather low specificity of the size 30 criterion. Anyway, differently from other authors, we do not consider this single criterion as sufficient for diagnosing malignancy and we always try to match it with other features. We give much relevance to the cortical changes, which can indicate an early stage of lymph node metastatization, eventually preceding the typical finding of a round and diffusely hypoechoic lymph node. We consider as indeterminate those lymph nodes exhibiting a diffuse but symmetric (circumferential) thickening of the cortex, as the only abnormality (Fig.11 on page ). We regard instead as highly suspicious those lymph nodes showing an asymmetric (unilateral) cortical thickening (Fig.12 on page, Fig.13 on page, Fig.14 on page ). We finally consider as overtly metastatic Page 6 of 23

7 the lymph nodes with a focal, eventually nodular, thickening of the cortex. This "nodule within the node" may vary in size from millimetric to a large deposit involving most of the lymph node (Fig.15 on page, Fig.16 on page, Fig.17 on page, Fig.18 on page, Fig.19 on page ). We also consider the changes within the central hyperechoic "hilum". The hilum region can be displaced, can be reduced in size, can become overtly inhomogeneous, or can 2 totally disappear (Fig.20 on page, Fig.21 on page ). A small hilum can be a non specific finding but in our experience a hilar displacement by an asymmetric or focal cortical thickening or a partial or total substitution of the hilum with hypoechoic tissue indicate metastasis. The borders of a metastatic lymph node are commonly described as being sharp, eventually irregular in most cases while reactive lymphadenopathy are said to show 12 both sharp or blurred margins. In our opinion the evaluation of the nodal border is too subjective, and we currently do not rely on the appearance of the borders to distinguish between reactive and metastatic lymph nodes. While most of the papers published on this topic only rely on the B-mode findings, we use color- and power-doppler imaging for any abnormal lymph node or subcutaneous lesion encountered. Benign lymph nodes show a monopolar vascularization, with vessels entering the lymph node hilum and distributing regularly toward the periphery (without reaching the nodal cortex). In malignant lymph nodes this "color hilum" is lost or displaced while multiple vessels penetrate the nodal capsule and enter the lymph node distributing 2,5,36 anarchically (Fig.22 on page, Fig.23 on page, Fig.24 on page ). We find Doppler US being particularly helpful in some indeterminateness circumstance, improving operator's confidence in suspecting malignancy. Images for this section: Page 7 of 23

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9 Fig. 1 Fig. 2: Fig.2 - Drawing of normal (A), fatty (C and D), and reactive (B) lymph nodes. Page 9 of 23

10 Fig. 3: Fig.3 - Fatty lymph node of the inguinal region. Note very thin, residual cortex peripherally. Page 10 of 23

11 Fig. 4: Fig.4 - Very large, fatty lymph node of the inguinal region. Page 11 of 23

12 Fig. 5: Fig.5 - Reactive lymph node of the inguinal region. Diffuse and homogeneous cortical thickening with hilar vascularization. Page 12 of 23

13 Fig. 6: Fig.6 - Drawing of the morphological and structural changes in metastatic lymph nodes. Page 13 of 23

14 Conclusion The diagnostic criteria employed in the literature to diagnose lymph node malignancy with US are frequently vague and contradictory. Few series estimate the accuracy of each sign and no series analyzes the intraobserver and interobserver variability of the US performance (which is notoriously an operator dependent modality) and of the US criteria. Many authors highlight how the reported results for the US lymph node assessment vary greatly in the literature: they try to explain somehow these inconsistencies but the differences in the diagnostic criteria employed are rarely considered. We believe that large, prospective series with state-of-art US equipments, specifically-trained operators, and most of all with strictly-stated and histologically-validated criteria are still needed. Images for this section: Page 14 of 23

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16 Fig. 1 Page 16 of 23

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18 16. Voit CA, van Akkooi AC, Schäfer-Hesterberg G, et al. Rotterdam Criteria for sentinel node (SN) tumor burden and the accuracy of ultrasound (US)-guided fine-needle aspiration cytology (FNAC): can US-guided FNAC replace SN staging in patients with melanoma? J Clin Oncol 2009; 27: Prayer L, Winkelbauer H, Gritzmann N, Winkelbauer F, Helmer M, Pehamberger H. Sonography versus palpation in the detection of regional lymph-node metastases in patients with malignant melanoma. Eur J Cancer 1990; 26: Blessing C, Feine U, Geiger L, Carl M, Rassner G, Fierlbeck G. Positron emission tomography and ultrasonography. A comparative retrospective study assessing the diagnostic validity in lymph node metastases of malignant melanoma. Arch Dermatol 1995; 131: Nazarian LN, Alexander AA, Rawool NM, Kurtz AB, Maguire HC, Mastrangelo MJ. Malignant melanoma: impact of superficial US on management. Radiology 1996; 199: Nazarian LN, Alexander AA, Kurtz AB, et al. Superficial melanoma metastases: appearances on gray-scale and color Doppler sonography. AJR 1998; 170: Binder M, Kittler H, Steiner A, Dorffner R, Wolff K, Pehamberger H. Lymph node sonography versus palpation for detecting recurrent disease in patients with malignant melanoma. Eur J Cancer 1997; 33: Rossi CR, Seno A, Vecchiato A, et al. The impact of ultrasound scanning in the staging and follow-up of patients with clinical stage I cutaneous melanoma. Eur J Cancer 1997; 33: Rossi CR, Mocellin S, Scagnet B, et al. The role of preoperative ultrasound scan in detecting lymph node metastasis before sentinel node biopsy in melanoma patients. J Surg Oncol 2003; 83: Blum A, Schlagenhauff B, Stroebel W, Breuninger H, Rassner G, Garbe C. Ultrasound examination of regional lymph nodes significantly improves early detection of locoregional metastases during follow-up of patients with cutaneous melanoma: results of a prospective study of 1288 patients. Cancer 2000; 88: Brountzos EN, Panagiotou IE, Bafaloukos DI, Kelekis DA. Ultrasonographic detection of regional lymph node metastases in patients with intermediate or thick malignant melanoma. Oncol Rep 2003; 10: Voit C, Mayer T, Kron M, et al. Efficacy of ultrasound B-scan compared with physical examination in follow-up of melanoma patients. Cancer 2001; 91: Voit C, Schoengen A, Schwürzer M, et al. Detection of regional melanoma metastases by ultrasound B-scan, cytology or tyrosinase RT-PCR of fineneedle aspirates. Br J Cancer 1999; 80: Voit C, Mayer T, Proebstle TM, et al. Ultrasound-guided fine-needle aspiration cytology in the early detection of melanoma metastases. Cancer 2000; 90: Page 18 of 23

19 29. Ulrich J, Voit C. Ultrasound in dermatology. Part II. Ultrasound of regional lymph node basins and subcutaneous tumours. Eur J Dermatol 2001; 11: Hocevar M, Bracko M, Pogacnik A, et al. The role of preoperative ultrasonography in reducing the number of sentinel lymph node procedures in melanoma. Melanoma Res 2004; 14: Testori A, Lazzaro G, Baldini F, et al. The role of ultrasound of sentinel nodes in the pre- and post-operative evaluation of stage I melanoma patients. Melanoma Res 2005; 15: Sibon C, Chagnon S, Tchakérian A, et al. The contribution of high-resolution ultrasonography in preoperatively detecting sentinel-node metastases in melanoma patients. Melanoma Res 2007; 17: Schäfer-Hesterberg G, Voit C. Ultrasound pre sentinel node dissection. Melanoma Res 2008; 18: Starritt EC, Uren RF, Scolyer RA, Quinn MJ, Thompson JF. Ultrasound examination of sentinel nodes in the initial assessment of patients with primary cutaneous melanoma. Ann Surg Oncol 2005; 12: Schmid-Wendtner M-H, Partscht K, Korting HC, Volkenandt M. Improved differentiation of benign and malignant lymphadenopathy in patients with cutaneous melanoma by contrast-enhanced color Doppler sonography. Arch Dermatol 2002; 138: Schmid-Wendtner MH, Paerschke G, Baumert J, Plewig G, Volkenandt M. Value of ultrasonography compared with physical examination for the detection of locoregional metastases in patients with cutaneous melanoma. Melanoma Res 2003; 13: Schmid-Wendtner MH, Dill-Müller D, Baumert J, et al. Lymph node metastases in patients with cutaneous melanoma: improvements in diagnosis by signal-enhanced color Doppler sonography. Melanoma Res 2004;14: Bafounta ML, Beauchet A, Chagnon S, Saiag P. Ultrasonography or palpation for detection of melanoma nodal invasion: a meta-analysis. Lancet Oncol 2004; 5: van Rijk MC, Jelle Teertstra H, Peterse JL, et al. Ultrasonography and fine-needle aspiration cytology in the preoperative evaluation of melanoma patients eligible for sentinel node biopsy. Ann Surg Oncol 2006; 13: Blum A, Schmid-Wendtner MH, Mauss-Kiefer V, Eberle JY, Kuchelmeister C, Dill-Müller D. Ultrasound mapping of lymph node and subcutaneous metastases in patients with cutaneous melanoma: results of a prospective multicenter study. Dermatology 2006; 212: Uren RF, Sanki A, Thompson JF. The utility of ultrasound in patients with melanoma. Expert Rev Anticancer Ther 2007; 7: Kunte C, Schuh T, Eberle JY, et al. The use of high-resolution ultrasonography for preoperative detection of metastases in sentinel lymph nodes of patients with cutaneous melanoma. Dermatol Surg 2009; 35: Page 19 of 23

20 43. Sanki A, Uren RF, Moncrieff M, et al. Targeted high-resolution ultrasound is not an effective substitute for sentinel lymph node biopsy in patients with primary cutaneous melanoma. J Clin Oncol 2009; 27: Personal Information Orlando Catalano, Dept of Radiology, National Cancer Institute "G.Pascale", Naples, Italy. Antonio Nunziata, Dept of Radiology, DSB 30, ASL Napoli 1 centro, Naples, Italy. Fabio Sandomenico, Dept of Radiology, National Cancer Institute "G.Pascale", Naples, Italy. Sergio Venanzio Setola, Dept of Radiology, National Cancer Institute "G.Pascale", Naples, Italy. Adolfo Gallipoli D'Errico, Dept of Radiology, National Cancer Institute "G.Pascale", Naples, Italy. Images for this section: Page 20 of 23

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