The role of ultrasonography guided-fine-needle-aspiration in subclinic axillary lymph node staging of breast cancer. Case series of 108 patients.

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1 The role of ultrasonography guided-fine-needle-aspiration in subclinic axillary lymph node staging of breast cancer. Case series of 108 patients. Poster No.: C-2585 Congress: ECR 2012 Type: Scientific Exhibit Authors: D. Fournier, D. Huber, C. Duc, T. Laswad, J. Moreau, A.-M. Villemain, N. Schneider; Sion/CH Keywords: Metastases, Biopsy, Ultrasound, Breast DOI: /ecr2012/C-2585 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 36

2 Purpose Pretreatment axillary US for early invasive breast cancer patients and needle sampling of morphologically abnormal lymph nodes are now widely recommended. The aim of our study was to evaluate the performance of US guided-fine-needleaspiration-cytology (FNAC) to detect metastasis in subclinical axillary lymph nodes in the initial staging and planning of treatment and to evaluate the subsequent percentage of sentinel lymph node biopsy procedures (SLNB) which were not necessary. The trend is: if a metastatic lymph node is proved, there is no reason to do SLNB and the patient has a one step surgery for the tumor ablation and the axillary lymph node dissection (ALND). Fig. 1: Right MLO mammography with a breast cancer and a nodular < 1 cm lymph node; preoperative markers within. Fine needle US-guided aspiration cytology of this small lymph node, with a morphologically benign appearance. Cytology result: carcinomatous cells. Background The current trend in oncologic breast surgery is to define treatment options to allow optimal care avoiding unnecessary interventions. Breast surgery has evolved from an extensive to a more conservative approach. Since 2000, many clinical trials have confirmed that sentinel lymph node biopsy (SLNB) is an accurate technique thereby avoïding a complete axillary lymph node dissection Page 2 of 36

3 (ALND) in selected patients while diminishing the incidence of arm and shoulder morbidity. Axillary lymph node status is the single most significant predictive factor for patients with invasive breast tumors. A positive sentinel lymph node requires a subsequent axillary lymph node dissection. Sparing a second axillary surgery is a current concern that has stimulated the development of other ways for the preoperative detection of node metastases through the use of imaging methods. Routine axillary US examination of axillary and other lymph nodes associated with breast cancer combined with FNAC of morphologically abnormal lymph nodes is an effective method to prove lymph node metastases prior to surgery. Detection of a clincal occult metastatic lymph node is of very high importance because its alters the stage of the disease: - from I to II (if a positive axilary node is proved = N1) - from I or II to IIIC (any N3). Notice that: - one positive subclavicular node = N3a - one positive internal mammary node + one positive axillary node = N3b - one positive supraclavicular node= N3c - patients with stage III disease are often selected for a neoadjuvant chemotherapy Images for this section: Page 3 of 36

4 Fig. 1: Right MLO mammography with a breast cancer and a nodular < 1 cm lymph node; preoperative markers within. Fine needle US-guided aspiration cytology of this small lymph node, with a morphologically benign appearance. Cytology result: carcinomatous cells. Page 4 of 36

5 Methods and Materials From January 2006 to December 2010, 144 consecutive patients with invasive breast cancer, clinical stage T1/2N0, were evaluated by axillary US with fine needle aspiration cytology (FNAC). Thirty-six patients were excluded due to: - metastatic breast cancer - DCIS - previous breast/axilla surgery - no lymph node visible on axillary US. All 108 remaining patients underwent initial percutaneaous breast microbiopsy confirming invasive malignancy. Axillary US and node FNAC were performed by the same breast radiologist (df) using high-resolution linear probes, 12 MHz of ATL HDI 500 Philips Healthcare (Netherlands) and superlinear 4-15 MHz of Aixplorer SuperSonic Imagine (Aix-en-Provence France). We classify the axillary lymph node (type 1 to 6) according to the criteria of Bedi et al. (AJR 2008; 191: ): Page 5 of 36

6 Fig. 2: Type 1, benign, lymph node in axillary region : very thin cortex, difficult to see (device : Aixplorer SuperSonic Imagine). Page 6 of 36

7 Fig. 3: Type 2, benign, lymph node in the axillary region: thin cortex< 3mm (device: ATL HDI 5000). Fig. 4: Type 3, benign, lymph node in the axillary region: regular cortex > 3mm, some lobulations (device : Aixplorer SuperSonic Imagine) Page 7 of 36

8 Fig. 5: Type 4, «benign», lymph node: diffuse lobulations of the cortex but, could also be a false negative (4/36 in the publication of Bedi) (device: ATL HDI 5000) Fig. 6: Type 5, metastatic, lymph node : irregular cortex, and/or hypoechoïc focal thickening/nodule (device : Aixplorer SuperSonic Imagine) Page 8 of 36

9 Fig. 7: Type 6, metastatic, lymph node: round, completely hypoechoïc Any lymph node type 4,5,6, was considered as abnormal and selected for FNAC. If more than one abnormal lymph node was found, the most suspicious one was selected as target. The three main criteria, grading from low to high probabilty of metastatic deposit in a lymph node, were: - hypoechoic avascular cortical asymetry < 3mm - cortical nodule (any size) deforming hilum= type 5 - completely hypoechoïc and round (any size) =type 6. If many lymph nodes were abnormal, the lowest one in the axilla was selected. Page 9 of 36

10 If only normal lymph nodes (type 2/3) were detected, the lowest one in the axilla was selected: the cortex on the inner part was the target for FNAC. The smallest target was 1.5 mm (see images below). Fig. 9: The smallest target in this series : a small lymph node morphologically benign type 3 5mm in thickness but with asymetric avascular hypoechoïc cortex (1.5 mm) in the deeper part: potential metastatic deposit? FNA was done in this region and the cytology was positive. One FNAC was done in one lymph node for 86 patients and in two for 22 patients (the second FNAC was done in a infra and/or supraclavicular and/or internal mammary abnormal lymph node). Each node was sampled only once. Material and technique for FNA Page 10 of 36

11 Fig. 8: Material: 20cc syringe with connector tube, 23g needle; CytoLyt container. Technique for FNA: 1. Position the needle within the target under US guidance. 2. Keep the needle inside the target during 1 min, even if bloody, with light rotation movements. 3. Remove the needle from the target. 4. Remove the syringe from the connector tube. 5. Aspirate 3-5 cc of CytoLyt fluid into the syringe. 6. Aspirate 5 cc of air into the syringe (vertically held). 7. Reattach the syringe to the connector tube. 5. Force fluid and alternately air (by changing the position of the syringe) to empty the syringe and to wash the needle contents into the CytoLyt container. Page 11 of 36

12 Fig. 29: Poster (in french) demonstrating the improvement of cytology results when using Cytolyt-ThinPrep method for FNAC of breast lesions ( 1999, 21es journées Nationales de la Société Française de Sénologie et de Pathologie Mammaire, Paris). All cytological samples were processed with the ThinPrep System, analyzed by a breast specialist cytopathologist and classified as: - insufficient for diagnosis - negative - positive for malignancy. Patients with a negative result or insufficient material for diagnosis were referred to sentinel lymph node biopsy (SLNB). If positive, the patient did not require the SLNB procedure and had a complete axillary lymph node dissection (ALND) at the same time as the tumorectomy. The management decisions were based on the clinical data and our FNAC results: 22 patients underwent neoadjuvant chemotherapy and 86 patients had primary surgery (mean age 58 and 54 years respectively). Patients with positive cytology or included in a neoadjuvant protocol had axillary lymph node dissection (ALND), while patients with negative or nondiagnostic cytologic results underwent sentinel lymph node biopsy (SLNB). Final histopathologic results (SLNB or axillary lymph node dissection) were compared with preoperative US-guided FNAC results. Page 12 of 36

13 Images for this section: Fig. 2: Type 1, benign, lymph node in axillary region : very thin cortex, difficult to see (device : Aixplorer SuperSonic Imagine). Page 13 of 36

14 Fig. 3: Type 2, benign, lymph node in the axillary region: thin cortex< 3mm (device: ATL HDI 5000). Fig. 4: Type 3, benign, lymph node in the axillary region: regular cortex > 3mm, some lobulations (device : Aixplorer SuperSonic Imagine) Page 14 of 36

15 Fig. 5: Type 4, «benign», lymph node: diffuse lobulations of the cortex but, could also be a false negative (4/36 in the publication of Bedi) (device: ATL HDI 5000) Fig. 6: Type 5, metastatic, lymph node : irregular cortex, and/or hypoechoïc focal thickening/nodule (device : Aixplorer SuperSonic Imagine) Page 15 of 36

16 Fig. 7: Type 6, metastatic, lymph node: round, completely hypoechoïc Fig. 8: Material: 20cc syringe with connector tube, 23g needle; CytoLyt container. Page 16 of 36

17 Fig. 29: Poster (in french) demonstrating the improvement of cytology results when using Cytolyt-ThinPrep method for FNAC of breast lesions ( 1999, 21es journées Nationales de la Société Française de Sénologie et de Pathologie Mammaire, Paris). Fig. 9: The smallest target in this series : a small lymph node morphologically benign type 3 5mm in thickness but with asymetric avascular hypoechoïc cortex (1.5 mm) in the deeper part: potential metastatic deposit? FNA was done in this region and the cytology was positive. Page 17 of 36

18 Fig. 11: Normal lymph node type 2. Fig. 12: Normal lymph node type 2 in the lower axillary region Page 18 of 36

19 Fig. 13: Invasive ductal carcinoma of the left breast (not shown). Axillary lymph node type 5. Positive FNAC, 23 Gauge needle (arrow). Fig. 14: Invasive lobular carcinoma with 2 metastatic lymph nodes after surgery. Positive FNAC in a lymph node type 5. Good correlation between surgery/mri/sonography. Page 19 of 36

20 Fig. 15: Carcinoma in the left breast. Only one lymph node with a 6.6 mm metastatic deposit visible on US with MRI correlation (coronal view with arrow). Positive FNAC, 23 Gauge needle. Fig. 24: Small nodule (2.7 mm) at the outer pole of a apparently norma lymph node. FNAC : malignant cells. Page 20 of 36

21 Results One hundred and eight patients had axillary lymph US-guided FNAC as a part of the investigation for invasive breast cancer. No immediate or delayed complications such as bleeding, hematoma, nerve injury, or infection were reported. Eighty- six patients underwent primary surgery and the other 22 underwent neoadjuvant chemotherapy with subsequent surgery. The median age was 58 (range 33-83) and 54 (range 33-71) years for the two groups, respectively. Study design Fig. 10: Study design. Results for both groups (neoadjuvant chemotherapy and surgery) Page 21 of 36

22 FNAC was positive for axillary metastases in 55 out of 108 patients (50.9%); in these cases we proceeded with ALND. FNAC was negative for 46 (42.6%). In seven (6.5%) cases the FNAC was insufficient for diagnosis (one case with only necrotic cells and in six other cases the specimen was considered insufficient): all these patients were considered to be negative for statistical analysis. False-negative results were documented in 18 (33.9%) out of these 53 patients (46 with negative cytology and 7 considered negative, but insufficient for diagnosis). Three patients had isolated tumor cells on definitive histology despite a negative FNAC. We did not consider these results as cytohistological discordances because pathological classification remains pn0(sn) and no further ALND was performed. The overall sensitivity was 73%, NPV 66%, specificity 85% and PPV 89%. The overall concordance between US-guided FNAC and definitive histologic diagnosis was 84%. For the patients in the primary surgery group, no false-positive result was documented. In the neoadjuvant chemotherapy group, 6 out of 18 patients with positive pretreatment FNAC had negative axillary lymph nodes; we have interpreted this apparent discrepancy as a complete node histological response and not as false-positive results. We focus now on the primary surgery group, for which the nodes were not affected by the neoadjuvant chemotherapy. Results for the primary surgery group (86 patients ) Page 22 of 36

23 Fig. 26: Study design for the 86 patients with primary surgery. Among the 35 patients with negative FNAC, 6 had ALND because of positive lymph node in the subclavicular region (3) et in the intra mammary region (3). Quantitative cytology results of the 36/86 positive FNAC : 94% with more than 200 malignant cells 30 > 1000 cells 4 > > > 50 (CLI with 1/15 positive lymph node after surgery) Page 23 of 36

24 1 < 50 (metastases of a CLI proved on immunohistochimistry) Among 86 FNAC there was only 3 micrometastases (0.2-2mm) on definitive histologic examination (=3 false negatives on FNAC). Fig. 25: 86 patients with primary surgery. Correlation between FNAC and histopathologic specimen. 14 false negatives FNAC : 2 insufficient material, 12 with normal/reactive lymphoïd cells (mainly in type 3, benign appearance, lymph nodes. Specificity 100% PPV 100% Sensitivity 77% NPV 71% 49/86 patients with negative FNAC had the sentinel lymph node biopsy (SLNB): - 14 positifs - 35 négatifs Page 24 of 36

25 Fig. 30: The different types and percentages of the lymph node at US examination. Fig. 27: Correlation between US LN type and FNAC results. Page 25 of 36

26 Fig. 28: Clinicopathological features of invasive carcinoma surgery group Page 26 of 36

27 Fig. 31: Comparison of spared sentinel node biopsy in the literature and in our study. The trend reached was a high percentage of patientswho were spared the sentinel lymph node biopsy (37/86 patients with positive FNAC = 43%) and costs saved were estimated up to euros. Some examples Fig. 17: Left breast cancer. Normal lymph nodes on mammography and US (type 2). Page 27 of 36

28 Fig. 18: Left breast cancer. One dense axillary lymph node on MLO mammography. US demonstrates a typical nodular metastasis inside the LN and a thin, compressed, cortex. Notice that this 16 mm metastasis is highly vascular. Page 28 of 36

29 Fig. 19: The same metastatic lymph node analyzed with two diffrent US device. Fig. 22: Left breast cancer with one positive (right picture: transverse view of FNAC ) internal mammary node (left picture: saggital view) and one positive axillary node = N3b. This patients had stage III disease and a neoadjuvant chemotherapy. Page 29 of 36

30 Fig. 20: Right breast cancer. Cortical asymetry in a small LN. FNA: malignant cells. Fig. 21: Multiple metastatic type 6 lymph nodes < 10 mm. FNAC: malignant cells. Page 30 of 36

31 Fig. 23: Right breast cancer. Small polar nodule. FNAC: malignant cells. Fig. 16: Left breast cancer. Typical type 6 lymph nodes but it was a pseudo metastatic one: multiple small ovalar and round LN in both axilla in a patient with systemic lupus erythematosus. FNAC : reactive cells only. No metastasis on definitive histology (SNB). Images for this section: Page 31 of 36

32 Fig. 25: 86 patients with primary surgery. Correlation between FNAC and histopathologic specimen. 14 false negatives FNAC : 2 insufficient material, 12 with normal/reactive lymphoïd cells (mainly in type 3, benign appearance, lymph nodes. Page 32 of 36

33 Fig. 10: Study design. Fig. 26: Study design for the 86 patients with primary surgery. Among the 35 patients with negative FNAC, 6 had ALND because of positive lymph node in the subclavicular region (3) et in the intra mammary region (3). Page 33 of 36

34 Conclusion The sonographic study combined with US guided-fnac of sub-clinical lymph nodes, sometimes smaller than 3 mm, provides essential information in the pretherapeutic staging and planning for invasive breast cancer. The specificity and the PPV were 100%, the sensitivity 77% and the NPV 71% in patients selected for primary surgery. The cyto-histologic concordance was 84%. In our study, its major benefit was to avoïd a second surgical intervention in 43% of these patients. Evaluating systematically all lymph node areas, the US combined with US guided-fnac allows also a better selection of patients for neoadjuvant chemotherapy if a positive lymph node is proved to be metastatic outside of the axillary region. To improve the results of US lymph nodes staging, we suggest, when there is no evidence of metastatic LN, to analyze the US " sentinel lymph node", searching for a cortical avascular area in a "morphologically normal" LN as a target for FNAC. References Tate JJ et al. Ultrasound detection of axillary lymph node metastases in breast cancer. Eur J Surg Oncol, 1989, 15(2): Avantages pratiques du transport en milieu liquide lors de ponction à l'aiguille fine des lésions du sein : à propos de750 ponctions dont 210 cancers. D. Fournier, F. Joris, J-L. Pauzé, G. Gaudin, J. Vogel. 1999, 21es journées Nationales de la Société Française de Sénologie et de Pathologie Mammaire, Paris. Praktische Vorteile des Transports in Flüssigkeit (Cytolyt) von Feinnadelpunktionen bei Brusterkrankungen : 750 Punktionen, 210 davon mit Krebsdiagnose. D Fournier F. Joris, J-L. Pauzé, G. Gaudin, J. Vogel. 2000, Erster Gemeinsamer Senologie Kongress der Deutschen-Österreichischen-Schweizer Gesellschaft für Senologie. Lugano. Cytologie des lésions du sein par ponction à l'aiguille : comparaison des potentialités du transport en milieu liquide et de l'analyse en couche mince par rapport à la méthode Page 34 of 36

35 traditionnelle d'étalement sur lames. F. Joris, J-L. Pauzé, D Fournier, G. Gaudin, J. Vogel. 2000, Erster Gemeinsamer Senologie Kongress der Deutschen-ÖsterreichischenSchweizer Gesellschaft für Senologie. Lugano. Oruwari JU et al. Axillary staging using ultrasound-guided fine needle aspiration biopsy in locally advanced breast cancer. Am J Surg, 2002, 184(4): Kuenen-Boumeester V et al. Ultrasound-guided fine needle aspiration cytology of axillary lymph nodes in breast cancer patients. A preoperative staging procedure. Eur J Cancer, 2003, 39 (2): Alvarez S et al. Role of sonography in the diagnosis of axillary lymph node metastases in breast cancer: a systematic review. AJR Am J Roentgenol, 2006, 186(5): Bedi D. et al. Cortical Morphologic Features of Axillary Lymph Nodes as a Predictor of Metastasis in Breast Cancer: In Vitro Sonographic Study. AJR 2008; 191: Jain A et al. The role of ultrasound-guided fine-needle aspiration of axillary nodes in the staging of breast cancer. Ann Surg Oncol, 2008, 15(2): Hinson JL et al. The critical role of axillary ultrasound and aspiration biopsy in the management of breast cancer patients with clinically negative axilla. Ann Surg Oncol, 2008, 15(1): Swinson C et al. Ultrasound and fine needle aspiration cytology of the axilla in the preoperative identification of axillary nodal involvement in breast cancer. Eur J Surg Oncol, 2009, 35 (11): Krishnamurthy S at al. Current applications and future prospects of fine-needle aspiration biopsy of locoregional lymph nodes in the management of breast cancer. Cancer, 2009, 117(6): Boughey JC et al. Cost modeling of preoperative axillary ultrasound and fine-needle aspiration to guide surgery for invasive breast cancer. Ann Surg Oncol, 2010, 17(4): MacNeill M et al. Fine needle aspiration cytology is a valuable adjunct to axillary ultrasound in the preoperative staging of breast cancer. J Clin Pathol, 2011, 64(1):42-46 Page 35 of 36

36 Jung J et al. Accuracy of preoperative ultrasound and ultrasound-guided fine needle aspiration cytology for axillary staging in breast cancer. ANZ J Surg, 2010, 80(4): Baruah BP et al. Axillary node staging by ultrasonography and fine-needle aspiration cytology in patients with breast cancer. Br J Surg, 2010, 97(5): Mainiero MB et al. Regional lymph node staging in breast cancer: the increasing role of imaging and ultrasound-guided axillary lymph node fine needle aspiration. Radiol Clin North Am,2010, 48(5): Park S et al. Impact of preoperative ultrasonography and fine-needle aspiration of axillary lymph nodes on surgical management of primary breast cancer. Ann Surg Oncol, 2011, 18 (3): Schiettecatte A et al. Initial axillary staging of breast cancer using ultrasound-guided fine needle aspiration: a liquid-based cytology study. Cytopathology, 2011, 22(1):30-35 Personal Information Dominique Fournier MD, radiologist at the Radiologic Institute, Rue du Scex 2, Sion 1950, Switzerland Founder and Medical Director of the 3R (Réseau Radiologic Romand) radiologic network. Formerly head of the ultrasound unit, Radiology Department, and teacher at the medecine faculty, University of Lausanne, Switzerland Page 36 of 36