SENTINEL LYMPH NODE BIOPSY IN BREAST CANCER procedural issues and prognostic impact of detecting micrometastases
Paul D. Gobardhan
Sentinel Lymph Node Biopsy in Breast Cancer: procedural issues and prognostic impact of detecting micrometastases Paul D. Gobardhan Thesis, University Utrecht, with a summary in Dutch Proefschrift, Universiteit Utrecht, met een samenvatting in het Nederlands ISBN: 978-94-6108-297-8 Cover: pgobardhan Lay-out and printed by: Gildeprint Drukkerijen, Enschede, the Netherlands © PD Gobardhan, 2012 None of the contents may be reproduced or transmitted in any form without the permission of the author or, when appropriate, the publishers of the published papers. Financial support for the publication of this thesis was provided by: Maatschap Chirurgie Diakonessenhuis Utrecht/Zeist, Raad van Bestuur Amphia ziekenhuis, Chirurgisch Fonds UMC Utrecht, Jansen-Cilag, Besnijdenis Centrum Nederland, Welmed, Chipsoft, Covidien, Abbot, Nycomed, Roche, Pfizer
SENTINEL LYMPH NODE BIOPSY IN BREAST CANCER procedural issues and prognostic impact of detecting micrometastases
Schildwachtklierprocedure bij borstkanker procedurele kwesties en voorspellende waarde van het opsporen van micrometastasen (met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 31 mei 2012 des middags te 2.30 uur
door
Paul Dewdath Gobardhan geboren op 3 oktober 1975 te Utrecht
Promotor:
Prof. dr. I.H.M. Borel Rinkes
Co-promotor:
Dr. Th. van Dalen
Contents Chapter 1
7
Introduction and outline of the thesis
Chapter 2
13
Ultrasound-guided sentinel node procedure of nonpalpable
breast carcinoma.
Nuclear Medicine Communications, 2012;33:80-83
Chapter 3
25
Discordance of intraoperative frozen section analysis with
definitive histology of sentinel lymph nodes in breast cancer
surgery: complementary axillary lymph node dissection is
irrelevant for subsequent systemic therapy.
Annals of Surgical Oncology, 2010;17:2690-2695
Chapter 4
Axillary reverse mapping (ARM): the need for selection of
41
patients.
Submitted
Chapter 5
Axillary recurrences after SLNB: A multicentre analysis and
53
follow-up of SLN negative breast cancer patients.
Submitted
Chapter 6
Prognostic value of micrometastases in sentinel lymph nodes
67
of patients with breast carcinoma: a cohort study.
Annals of Oncology, 2009;20:41-48
Chapter 7
Prognostic value of micrometastases in sentinel lymph nodes
91
of patients with breast carcinoma: a multicenter cohort study.
Annals of Surgical Oncology, 2011;18:1657-1664
Chapter 8
Summary and general discussion
113
Chapter 9
125
Summary in Dutch (samenvatting in het Nederlands)
Chapter 10
133
Acknowledgements (dankwoord)
137
List of publications
141
Curriculum vitea auctoris
1 Introduction
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R34 8 | Chapter 1
Introduction Surgical treatment of breast cancer has evolved from Halsted’s radical mastectomy to
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breast conserving surgery. Similarly, surgical treatment of regional lymph nodes has
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also become less extensive. Axillary lymph node dissection (ALND) was standard of
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care for a long time and considered necessary for locoregional control as well as for
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staging purposes1,2. While ALND came with substantial morbidity1,3 and the majority
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of the ALND patients were “node negative”, various studies reported no effect of
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ALND on disease free and overall survival .
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4
R10 Sentinel lymph node biopsy: less extensive surgery
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In the mid-nineties the sentinel lymph node biopsy (SLNB) was introduced for staging
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in breast cancer patients. Conceptually, the search for sentinel lymph nodes (SLNs) in
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cancer patients was not new. In 1959 Gould presented his results of SLNB in patients
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treated for cancer of the parotis5 followed by a report describing the retrieval of SLNs
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in penile cancer6. Two decades later Morton popularized the use of SLNB in melanoma
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patients . In 1994 it was Giuliano, working in the same institute as Morton, who first
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described the use of the procedure in breast cancer patients . Shortly thereafter the
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SLNB was introduced in the Netherlands
. The frequency of using SLNB in breast
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cancer patients increased from 8.8% in 1998 to 70.6% in 2003 in the Netherlands
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(figure 1) . Nowadays this procedure is standard of care in clinically node negative
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breast cancer patients .
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9,10
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R30 Figure 1: Type of axillary surgery for 35,465 breast cancer patients in 1998–2003 in the Netherlands.
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R34 Introduction | 9
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SLN examination: more extensive pathology
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Regional lymph node status is an important prognosticator in patients with breast
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cancer. Concomitant with the introduction of the SLNB the examination of the
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harvested nodes was intensified. Pathological examination was refined by adding
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immunohistochemical staining (IHC) to conventional haematoxylin and eosine (H&E)
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and by serial sectioning of the lymph nodes. Since the introduction of the SLNB the
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frequency of minimal lymph node involvement has increased substantially (figure
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2)11. The frequent observation of ever smaller tumor deposits within SLNs has
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refuelled the discussion about its clinical relevance13.
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Figure 2: Increase of finding of micrometastatic disease since the introduction of the SLNB (as a proportion of all lymph node positive patients).
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Outline of the thesis
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This thesis describes a number of clinical questions that arised following the
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introduction of the SLNB. In the first four chapters of the thesis a number of
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procedure-associated issues are evaluated, in the last two chapters the clinical
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relevance of micrometastatic lymph node involvement is studied.
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As lymph node involvement is the main indicator for adjuvant systemic or
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locoregional therapy, lymph node staging has to provide optimal information.
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Different radiofarmacon injection techniques, parenchymal vs. peri-areolar, come
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with different visualization patterns. In chapter 2 we discuss the role of the ultrasound
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guided SLNB procedure for palpable and nonpalpable lesions to achieve a uniform
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staging procedure.
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During SLNB harvested nodes can be examined by frozen section (FS) analysis, enabling a complementary ALND during the same operation in case of a positive SLN. The role of FS analysis in SLNB is discussed in chapter 3, with a particular interest in
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the clinical implications of “discordant results”, i.e. a FS analysis result suggesting the
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absence of metastases and a definitive pathology result demonstrating the presence
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of lymph node metastases.
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Recently, there has been interest in the different lymphatic drainage patterns of the
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breast and arm, both convening in the axilla. Conceptually arm lymphatics might be
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spared when performing ALND for a breast disorder. Different techniques are being
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developed to visualize the different lymphatics (ARM: axillary reverse mapping).
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In chapter 4 we describe the results of a feasibility study on ARM in breast cancer
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patients with proven lymph node metastases.
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R14 The SLNB procedure has a high sensitivity regarding the presence of lymph node
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metastases. But patients with a “false-negative” SLN, may develop overt lymph node
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metastases at some time during follow-up. In chapter 5 the ipsilateral axillary relapse
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rate folllowing a negative SLNB was studied in a multi-institutional cohort.
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R19 Ever since the finding of lymph node micrometastases in breast cancer patients there
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has been debate on their prognostic value and this debate started well before the
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introduction of SLNB. Studies based on data from SLNB patients are scarce. In chapter
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6 we describe the prognostic significance of micrometastases in a prospective single
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center study and in chapter 7 data were collected from seven different hospitals.
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R34 Introduction | 11
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References
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1.
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Versus Standard Axillary Treatment in Operable Breast Cancer: The ALMANAC Trial. J Natl Cancer
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Mansel RE, Fallowfield L, Kissin M, et al. Randomized Multicenter Trial of Sentinel Node Biopsy
Inst 2006;98:599-609 2.
Samphao S, Eremin JM, El-Sheemy M, Eremin O. Management of the axilla in women with
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breast cancer: current clinical practice and a new selective targeted approach. Ann Surg Oncol
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2008;15:1282-1296
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3.
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Petrek JA, Heelan MC. Incidence of breast carcinoma-related lymphedema. Cancer 1998;83:27762781
4.
Pepels MJ, Vestjens JH, de Boer M, Smidt M, van Diest PJ, Borm GF, Tjan-Heijnen VC. Safety of
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avoiding routine use of axillary dissection in early stage breast cancer: a systematic review. Breast
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Cancer Res Treat 2011;125:301-313
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5.
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Gould EA, Winship T, Philbin PH, Kerr HH. Observations on a ‘sentinel node’ in cancer of the parotid. Cancer 1960;13:77-78
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6.
Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977;39:456-466
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7.
Morton DL, Wen DR, Wong JH et al. Technical details of intraoperative lymphatic mapping for early
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stage melanoma. Arch Surg 1992;127:392-399 8.
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Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391-398
9.
Meijer S, Pijpers R, Borgstein PJ, Bleichrodt RP, Diest PJ van. De schildwachtklierprocedure:
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standaardingreep bij de chirurgische behandeling van het mammacarcinoom. Ned Tijdschr
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Geneeskd 1998;142:2235-2237
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10. Borgstein PJ, Pijpers R, Comans EF, van Diest PJ, Boom RP, Meijer S. Sentinel lymph node biopsy in
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breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll
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Surg. 1998;186:275-283
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11. Ho VKY, van der Heiden-van der Loo M, Rutgers EJT, et al. Implementation of sentinel node biopsy in breast cancer patients in the Netherlands. Eur J Can 2008;44:683-691
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12. Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline
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recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol
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2005;23:7703-7720
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13. Patani N, Mokbel K. The clinical significance of sentinel lymph node micrometastasis in breast cancer. Breast Cancer Res Treat 2009;114:393-402
R34 12 | Chapter 1
2 Ultrasound-guided sentinel node procedure of nonpalpable breast carcinoma Paul D. Gobardhan Eva V.E. Madsen Thijs van Dalen Cornelis I. Perre Vivian Bongers Department of Surgery, Amphia hospital Breda Department of Surgery, Diakonessenhuis Utrecht Department of Nuclear Medicine, Diakonessenhuis Utrecht
Nuclear Medicine Communications, 2012;33:80-83
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Abstract
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Background: Peritumoral and peri-areolar tracer injection techniques lead to
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different lymphatic drainage in sentinel lymph node biopsy (SLNB) procedures. In
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a prospective study the visualization and identification rate of the ultrasound (US)
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guided tracer injection technique for palpable and nonpalpable breast tumors was
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evaluated.
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Patients and Methods: In 1262 consecutive patients with cT1-2N0 breast cancer
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patients SLNB was done following peritumoral tracer injection. In case of nonpalpable
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breast lesions
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probe. In case of ultrasonographically non-visible micro-calcifications the US-guided
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injection technique was wire-guided.
Tc nanocolloid injections were given using a 7.5 MHz ultrasound
99m
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Results: In 331 patients with nonpalpable breast lesions (26.2%), the
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lymphoscintigraphic visualization and surgical retrieval rate of axillary SLNs was
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98.5% and 99.4% respectively. For internal mammary (IM) SLNs these rates were
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21.1% and 17.8% respectively. These rates were similar in patients with palpable and
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nonpalpable tumors. Axillary metastases were detected in 38.7% of the patients with
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palpable tumors vs 16.5% of those with nonpalpable tumors (P < 0.001), while IM
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metastases were found in 4.8% and 3.0% respectively (P = 0.165).
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Conclusion: In nonpalpable breast lesions the US guided injection technique is an
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accurate technique for SLN identification and retrieval. The substantial rates of IM
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metastases in both palpable and nonpalpable lesions favour a peritumoral tracer
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injection technique.
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R34 14 | Chapter 2
Introduction
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The sentinel lymph node biopsy (SLNB) has become a widely accepted procedure for
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staging the axilla in cT1-2N0 breast cancer patients and is a safe and accurate concept1-3.
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Part of the SLNB-procedure is the radiotracer injection for preoperative visualization
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of sentinel lymph nodes (SLNs) on lymphoscintigraphy. Varying tracer injection
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techniques correlate with different lymphatic drainage patterns. In comparison
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to the peri-areolar tracer injection more internal mammary (IM) lymph nodes are
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visualized on lymphoscintigraphy when peri- or intratumoral tracer injections are
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used . Since metastatic IM lymph node involvement may have clinical implications
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some therefore advocate intra- or peritumoral radiotracer injection.
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lesions pose a challenge. Using a peri-areolar injection technique, resulting in a lower
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proportion of visualized IM nodes, is an inconsistent alternative. Using a wire-guided
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injection technique or ultrasound (US) to inject the radiotracer offers the advantage
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of providing a uniform procedure in both palpable and nonpalpable lesions. In the
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EANM procedural guidelines for nonpalpable lesions the use of US is suggested .
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identification rate in SLNB with US guided tracer injection for patients with palpable
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and nonpalpable breast cancers.
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Patients and Methods
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cancer patients underwent SLNB in our hospital. Patients who presented with a
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synchronous contralateral breast cancer (n = 31), multifocal carcinoma (n = 59),
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previous history of breast cancer in the ipsilateral breast (n = 23), previous diagnostic
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excisional biopsy (n = 35), unknown palpable or nonpalpable status (n = 33) or a
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combination of these criteria (n = 13) were excluded. The palpable/nonpalpable
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R34 Ultra-sound guided sentinel lymph node procedure | 15
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status was determined by the consulting surgeon at the first outpatient clinic visit.
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The cohort available for analysis consisted of 1262 patients, and 331 of them had a
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nonpalpable lesion (26.2%).
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Demographic data and information regarding preoperative lymphoscintigraphy,
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the operative procedure and pathology results were collected prospectively. The
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ethical committee of the hospital approved the routine use of the SLNB as a staging
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procedure. All patients received oral and written information regarding the SLNB
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procedure.
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Lymphoscintigraphy
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Lymphoscintigraphy was performed on the day of surgery. All patients received
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a combination of peritumoral and subcutaneous injections with 80 MBq
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nanocolloid (Nanocoll, GE Health) in a total volume of 0,6 ml physiologic saline,
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usually given in 3 equal doses. The subcutaneous injection was given in the area
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above the tumor. Peritumoral injections were guided by a 7.5 MHz US probe (Aloka),
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in both palpable and nonpalpable lesions. In case of ultrasonographically non-
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visible densities or micro-calcifications the US guided injection technique followed
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placement of a guide-wire. The wire was placed by mammographic aid preceding the
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nanocolloid injection on the same day as the planned SLNB. Using US for visualizing
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the moveable tip of the wire the nanocolloid depot was placed near the tip of the
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wire and thereby in the vicinity of the density or the area of micro-calcifications. The
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nuclear medicine specialist performed both the injection of the nanocolloid and the
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ultrasonography while guide-wires were placed by the radiologist.
Tc
99m
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Following tracer injection the area was massaged and semi-dynamic images were
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obtained until visualization of the first draining lymph node. As soon as the lymph
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channel to the first draining lymph node was visible, acquisition was started and
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anterior and lateral pictures with and without 57Co flood source was performed.
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Static images were obtained approximately two hours after injection depending
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on the time of surgery. Two minutes images were obtained with gamma camera (a
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Toshiba 901 HG single-head gamma camera before 2004 and a Philips skylight double-
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head gamma camera since 2004) using low energy high-resolution collimators. The
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R34 16 | Chapter 2
images were performed with and without a 57Co flood source. Using a handheld γ-ray
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detection probe (Europrobe, PI Medical diagnostic equipment BV) a skin mark was
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placed in the axilla (and parasternal when applicable).
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Surgery SLNB was done using the combination of a γ-ray detection probe in all cases and
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patent blue dye regularly. During the surgical procedure SLNs were retrieved first
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(both axillary and IM SLNs). Intraoperative frozen section (FS) analysis of the axillary
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SLNs was performed routinely to enable axillary lymph node dissection (ALND) during
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the same operative procedure. In case of IM SLNs visualized on lymphoscintigraphy
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an intercostal exploration was performed to retrieve these nodes.
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Tumorectomy was performed after SLNB. In case of palpable tumors this procedure
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was based on palpation, in case of nonpalpable lesions US or wire-guided (in case of
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micro-calcifications) excision was performed.
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R15 Pathology
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The definitive pathological examination was done according to the Dutch national
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guidelines . Specimen mammography was performed in case of micro-calcifications.
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Apart form intraoperative FS analysis of axillary SLNs, SLNs were formalin-fixed,
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paraffin embedded and at least three cuts from both halves were taken at 250 mm
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intervals starting from the center. Cuts were stained both with haematoxylin and
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eosin (H&E) and immunohistochemically (IHC) with an antibody against keratin (CK-
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8). When axillary SLNs contained micro- or macrometastases, patients were advised
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to undergo a complementary ALND. Lymph nodes retrieved by ALND were processed
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by examining one central cut from every lymph node. Primary tumors were classified
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by tumor size, Estrogen- (ER) and Progesterone- (PR) receptorstatus, modified Bloom
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and Richardson (BR) grade and the Mitotic Activity Index (MAI). Before 2004, Her-2-
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neu receptor-status (Her2/neu) was not routinely examined.
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7
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with palpable and nonpalpable tumors. Furthermore the proportions of patients
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with metastases in axillary and IM SLNs was compared.
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R34 Ultra-sound guided sentinel lymph node procedure | 17
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Statistical analysis
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Statistical analyses were performed using the SPSS, version 18.0 (SPSS, Inc., Chicago,
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USA). Chi-square analysis was performed to evaluate differences in axillary and IM
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SLN visualization and surgical retrieval rates between patients with palpable and
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nonpalpable lesions. P values of ≤ 0.05 were considered significant.
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Results
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The median age of the 1262 patients was 57 years, there were 931 (73.8%) patients
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with a palpable breast lesion and 331 (26.2%) with a nonpalpable breast lesion.
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Palpable breast cancers had a median diameter of 1.8 cm while nonpalpable breast
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cancer had a median diameter of 1.1 cm (P < 0.001). Baseline characteristics are
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shown in table 1.
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In the total population of 1262 patients the lymphoscintigraphic visualization rate
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for axillary SLNs was 99.0% (99.2% for palpable vs 98.5% for nonpalpable lesions, P =
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0.22). The axillary SLNs surgical retrieval rate was 99.2% in the total population and
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higher than the lymphoscintigraphic visualization rate due to the yield of patent blue
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in cases where lymphoscintigraphy did not show axillary SLNs (99.1% for palpable
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vs 99.4% for nonpalpable lesions, P = 0.65). For IM SLNs the lymphoscintigraphic
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visualization rates were similar in the two groups (21.4% for palpable vs 21.1% for
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nonpalpable tumors, P = 0.93). The IM SLNs surgical retrieval rate was comparable
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too: 17.3% in patients with palpable tumors and 17.8 in patients with nonpalpable
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tumors (P = 0.22; table 2). In the group of patients with nonpalpable cancers (n
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= 331), the primary tumors were visualized and removed with US in 259 (78.2%)
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patients while the remaining 72 (21.8%) patients had cancers that were removed
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following guide-wire placement.
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Table 1. Baseline characteristics for 1262 breast cancer patients Characteristic Age (years)
a
< 50 50-59 60-69 ≥ 70 Tumor size (cm)b Tumor size (%) < 1cm 1-2 cm 2-3 cm ≥ 3 cm unknown Bloom-Richardson grade (%) Well differentiated Moderately differentiated Poorly differentiated Unknown Mitotic Activity Indexb Mitotic Activity Index (%) < 10 ≥ 10 unkown Estrogen Receptor positive (%) Progesterone Receptor positive (%) Her2/neu Receptor positive (%)
Primary tumor Total Nonpalpable Palpable (n = 1262) (n = 331) (n = 931) 60.0 61.7 59.3 (+/- 12.8) (+/- 8.6) (+/- 14.0) 24.7% 8.2% 30.6% 26.9% 35.3% 24.0% 22.6% 35.3% 18.0% 25.8% 21.1% 27.4% 1.6 1.1 1.8 (0.02 – 6.50) (0.02 – 4.90) (0.15 – 6.50) 13.7% 52.6% 24.2% 8.6% 0.8%
34.1% 58.0% 6.0% 0.9% 0.9%
6.4% 50.7% 30.7% 11.4% 0.8%
43.7% 37.2% 17.6% 1.4% 4 (0-169)
57.7% 32.9% 7.6% 1.8% 2 (0-45)
38.8% 38.8% 21.2% 1.3% 5 (0-169)
70.8% 24.2% 4.9% 85.3% 66.6% 9.2%
83.7% 10.6% 5.7% 90.3% 65.0% 8.5%
66.3% 29.1% 4.6% 83.5% 67.2% 9.5%
R1 R2 P 0.003c
< 0.001e < 0.001d
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2
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R20 < 0.001e 0.007e 0.395e 0.045e
Mean (standard deviation) b Median (range) c Students T-test d Mann-Whitney U e Chi-square
a
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R34 Ultra-sound guided sentinel lymph node procedure | 19
Table 2. Visualization and retrieval rates for both axillary and internal mammary (IM) sentinel lymph nodes in 1262 breast cancer patients Primary tumor Total Palpable Nonpalpable Pb (n = 1262) (n = 931) (n = 331) Visualization (%)a Axillary 1250 (99.0) 924 (99.2) 326 (98.5) 0.22 IM 269 (21.3) 199 (21.4) 70 (21.1) 0.93
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Surgical retrieval (%) Axillary IM
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a b
1252 (99.2) 220 (17.4)
923 (99.1) 161 (17.3)
329 (99.4) 59 (17.8)
0.65 0.22
Lymphoscintigraphic visualization Chi-square
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Regional lymph node metastases were detected in axillary SLNs in 38.7% in the group
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of patients with palpable tumors and in 16.5% in the group with nonpalpable lesions
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(P < 0.001). IM lymph node metastases were detected in 4.8% of the patients with
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palpable tumors and in 3.0% of the patients with nonpalpable tumors (P = 0.165).
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Discussion
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In the present cohort study lymphoscintigraphic visualization and surgical retrieval
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rates were similar in patients with palpable and nonpalpable breast tumors when a US
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guided peritumoral injection technique was used. Axillary lymph node visualization
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and surgical retrieval rates were consistently high and IM SLNs were visualized and
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retrieved in a substantial proportion of the patients with palpable and nonpalpable
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cancers too.
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The main strengths of the present study are the uniformly performed procedure of
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the SLNB and the prospectively collected data. A weakness of the study is its single
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center nature. In our hospital all of the attending nuclear medicine specialists have
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been using US since the introduction of the SLNB but US guided radiotracer injection
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may be considered a difficult procedure for those nuclear medicine specialists not
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experienced in the use of US. Then, again, this may easily be overcome when nuclear
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medicine specialists collaborate with radiologists.
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R34 20 | Chapter 2
The reported visualization and surgical detection rates of patients with nonpalpable
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tumors are high, comparable to patients with palpable tumors and in line with
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current literature. Using the same combined peritumoral and subdermal injection
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technique, Sanli et al. reported a slightly lower success rate (93.2%) detecting
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axillary SLNs in patients with palpable breast lesions using
Tc rhenium sulphide
99m
colloid as a radiotracer9, while van Rijk et al. showed comparable results (97%)
2
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using a intratumoral injection only technique with 99mTc nanocolloid in patients with
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10
nonpalpable lesions and using an US or stereotaxic guided injection . Maza et al.
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found also similar result with a visualization rate of 96% using
Tc nanocolloid
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99m
peritumoral in patients with palpable breast lesions . As described by Tuttle et al.
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in a review report in 2001, there are several pros and cons for the different injection
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techniques for the radioactive tracer . Subcutaneous or subareolar injections are
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simple procedures with a high (axillary) SLN identification rate13 and an acceptable
R13
false-negative rate. The main disadvantage of skin/subareolar injection technique
R14
is that IM nodes may not be identified. These nodes receive their primary drainage
R15
from the deep parenchymal lymphatics of the breast and therefore skin/subareolar
R16
injection rarely detects IM nodes
. The peritumoral injection technique has been
R17
described as a more difficult procedure with a lower (axillary) SLN-identification
R18
rate
when compared to skin/subareolar injections. In addition, a higher false
R19
negative rate and a significant learning curve have been reported . The reported
R20
results contradict this disadvantage of a peritumoral injection technique.
R21
11
12
16,17
14,15
17
R22 SLNB should serve optimal staging of regional lymph nodes. The additional use of
R23
non-surgical therapy is to an important extent based on regional lymph node status.
R24
Although adjuvant systemic therapy is rarely adjusted based on tumor-positive
R25
IM lymph nodes, the radiotherapeutic treatment may be altered in a substantial
R26
proportion of patients based on the presence or absence of metastases in IM
R27
SLNs
. In the present study IM positive lymph nodes were observed in 4.8% of the
R28
patients with palpable cancers and in 3.0% of the patients with nonpalpable lesions.
R29
The presence of IM lymph node metastases underscores the importance of IM SLN
R30
sampling. As a consequence, intra- or peritumoral tracer injections are in our view
R31
the preferable method of radioactive tracer injection.
R32
4,18-20
R33
R34 Ultra-sound guided sentinel lymph node procedure | 21
R1
In conclusion, using the US guided tracer injection technique for nonpalpable breast
R2
tumors, axillary and IM SLNs were observed and retrieved in a high proportion of
R3
patients, similar to the rates of patients with palpable tumors. Another advantage
R4
of using a consistent tracer injection technique, in both palpable and nonpalpable
R5
lesions, is the use of a uniform procedure in all breast cancer patients with an
R6
indication for SLNB. US guided peritumoral tracer injection seems an appealing
R7
technique.
R8 R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
R31
R32
R33
R34 22 | Chapter 2
References
R1 R2
1.
Borgstein PJ, Pijpers R, Comans EF, van Diest PJ, Boom RP, Meijer S. Sentinel lymph node biopsy in
R3
breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll
R4
Surg 1998;186:275-283 2.
3.
4.
5.
6.
7.
8.
9.
Giuliano AE, Haigh PI, Brennan MB, Hansen NM, Kelley MC, Ye W, et al. Prospective observational
2
R5 R6
study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel
R7
node negative breast cancer. J Clin Oncol 2000;18:2553-2559
R8
Mansel RE, Fallowfield L, Kissin M, Goyal A, Newcombe RG, Dixon JM, et al. Randomized Multicenter
R9
Trial of Sentinel Node Biopsy Versus Standard Axillary Treatment in Operable Breast Cancer: The
R10
ALMANAC Trial. JNCI 2006;98:599-609
R11
Paredes P, Vidal-Sicart S, Zanon G, Pahisa J, Fernandez PL, Velasco M, et al. Clinical relevance of
R12
sentinel lymph nodes in the internal mammary chain in breast cancer patients. Eur J Nucl Med Mol
R13
Imaging 2005;32:1283-1287
R14
Nieweg OE, Estourgie SH, van Rijk MC, Kroon BB. Rationale for superficial injection techniques in
R15
lymphatic mapping in breast cancer patients. J Surg Oncol 2004;15;87:153-156
R16
Buscombe J, Paganelli G, Burak ZE, Waddington W, Maublant J, Prats E, et al. Sentinel node in breast
R17
cancer procedural guidelines. Eur J Nucl Mol Med Imaging 2007;34:2154-2159
R18
Rutgers EJ, Nortier JW, Tuut MK, van Tienhoven G, Struikmans H, Bontenbal M, et al. [Dutch Institute
R19
for Healthcare Improvement guideline, ‘‘Treatment of breast cancer’’]. Ned Tijdschr Geneeskd
R20
2002;146:2144-2151
R21
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. The value of histological grade in
R22
breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19:403-
R23
410
R24
Sanli Y, Berberoglu K, Turkmen C, Ozmen V, Muslumanoglu M, Igci A, et al. The value of combined
R25
peritumoral and subdermal injection techniques for lymphoscintigrapy in detection of sentinel
R26
lymph node in breast cancer. Clin Nucl Med 2006;31:690-693
R27
10. van Rijk MC, Tanis PJ, Nieweg OE, Loo CE, Olmos RA, Oldenburg HS, et al. Sentinel node biopsy
R28
and concomitant probe-guided tumor excision of nonpalpable breast cancer. Ann Surg Oncol
R29
2007;14:627-632
R30
R31
R32
R33
R34 Ultra-sound guided sentinel lymph node procedure | 23
R1
11. Maza S, Valencia R, Geworski L, Zander A, Guski H, Winzer KJ, et al. Peritumoural versus subareolar
R2
administration of technetium-99m nanocolloid for sentinel lymph node detection in breast cancer:
R3
preliminary results of a prospective intra-individual comparative study. Eur J Nucl Med Mol Imaging
R4
2003;30:651-656
R5 R6 R7 R8
12. Tuttle TM, Zogakis TG, Dunst CM, Zera RT, Singletary SEl. A review of technical aspects of sentinel lymph node identification for breast cancer. J Am Coll Surg 2002;195:261-268 13. Tuttle TM, Colbert M, Christensen R, Ose KJ, Jones T, Wetherille R, et al. Subareolar injection of 99mTc facilitates sentinel lymph node identification. Ann Surg Oncol 2002;9:77-81
R9
14. Clímaco F, Coelho-Oliveira A, Djahjah MC, Gutfilen B, Correia AH, Noe R, et al. Sentinel lymph
R10
node identification in breast cancer: a comparison study of deep versus superficial injection of
R11
radiopharmaceutical. Nucl Med Commun 2009;30:525-532
R12
15. Shimazu K, Tamaki Y, Taguchi T, Motomura K, Inaji H, Koyama H, et al. Lymphoscintigraphic
R13
visualization of internal mammary nodes with subtumoral injection of radiocolloid in patients with
R14
breast cancer. Ann Surg 2003;237:390-398
R15
16. Lin KM, Patel TH, Ray A, Ota M, Jacobs L, Kuvshinoff B, et al. Intradermal radioisotope is superior
R16
to peritumoral blue dye or radioisotope in identifying breast cancer sentinel nodes. J Am Coll Surg
R17
2004;199:561-566
R18
17. McMasters KM, Wong SL, Martin RC 2nd, Chao C, Tuttle TM, Noyes RD, et al. Dermal injection of
R19
radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy:
R20
results of a multiinstitutional study. Ann Surg 2001;233:676-687
R21
18. Madsen E, Gobardhan P, Bongers V, Albregts M, Burgmans J, de Hooge P, et al. The impact on post-
R22
surgical treatment of sentinel lymph node biopsy of internal mammary lymph nodes in patients with
R23
breast cancer. Ann Surg Oncol 2007;14:1486-1492
R24
19. Carcoforo P, Sortini D, Feggi L, Feo CV, Soliani G, Panareo S, et al. Clinical and therapeutic importance
R25
of sentinel node biopsy of the internal mammary chain in patients with breast cancer: a single-
R26
center study with long-term follow-up. Ann Surg Oncol 2006;13:1338-1343
R27
R28
20. Leidenius MH, Krogerus LA, Toivonen TS, Leppanen EA, von Smitten KA. The clinical value of parasternal sentinel node biopsy in breast cancer. Ann Surg Oncol 2006;13:1-6
R29
R30
R31
R32
R33
R34 24 | Chapter 2
3 Discordance of intraoperative frozen section analysis with definitive histology of sentinel lymph nodes in breast cancer surgery: complementary axillary lymph node dissection is irrelevant for subsequent systemic therapy Dorien Geertsema Paul D. Gobardhan Eva V.E. Madsen Mirjam Albregts Joost van Gorp Pieter de Hooge Thijs van Dalen Department of Surgery, Diakonessenhuis Utrecht Department of Radiotherapy, University Medical Center Utrecht Department of Pathology, Diakonessenhuis Utrecht Department of Nuclear Medicine, Diakonessenhuis Utrecht Annals of Surgical Oncology, 2010:17;2690-2695
R1
Abstract
R2 R3
Background: In breast cancer surgery, intraoperative frozen section (FS) analysis of
R4
sentinel lymph nodes (SLNs) enables axillary lymph node dissection (ALND) during
R5
the same operative procedure. In case of discordance between a “negative” FS
R6
analysis and definitive histology, an ALND as a second operation is advocated since
R7
additional lymph node metastases may be present. The clinical implications of the
R8
subsequent ALND in these patients were evaluated.
R9
R10
Patients and Methods: Between November 2000 and May 2008, 879 consecutive
R11
breast cancer patients underwent surgery including sentinel lymph node biopsy
R12
(SLNB) with intraoperative FS-analysis of two central cuts from axillary SLNs. Following
R13
fixation and serial sectioning, SLNs were further examined postoperatively with
R14
haematoxylin and eosine- and immunohistochemical techniques. For patients with
R15
a discordant FS examination the effect of the pathology findings of the subsequent
R16
ALND-specimen on subsequent non-surgical therapy were evaluated.
R17
R18
Results: FS analysis detected axillary metastases in the SLN(s) in 200 patients (23%),
R19
while the definitive pathology examination detected metastases in SLNs in another
R20
151 patients (17%). A complementary ALND was performed in 108 of the 151 patients
R21
with discordant FS. Additional tumor positive axillary lymph nodes were found in
R22
17 patients (16%), leading to ‘upstaging’ in seven (6%). Subsequent non-surgical
R23
treatment was adjusted in four patients (4%): all four had more extensive locoregional
R24
radiotherapy, no patient received additional hormonal- and/or chemotherapy.
R25
R26
Conclusion: Discordance between intraoperative FS analysis and definitive histology
R27
of SLNs is common. In this selection of patients, a substantial proportion had
R28
additional lymph node metastases, but post-surgical treatment was rarely adjusted
R29
based on the findings of the complementary ALND.
R30
R31
R32
R33
R34 26 | Chapter 3
Introduction
R1 R2
Sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection
R3
(ALND) for assessing axillary lymph node status in breast cancer patients1,2.
R4
Subsequent ALND is done only when the SLN contains metastases because of the
R5
risk of additional lymph node metastases in the non-SLNs in the axilla3,4.
R6 R7
Intraoperative frozen section (FS) analysis of axillary SLNs enables prompt detection of lymph node metastases. As a result, ALND can be done during the same operative
3
R8 R9
procedure. Despite a “negative” FS result, definitive pathology examination of the
R10
SLN will reveal metastases in a number of patients, inherent to the more extensive
R11
work-up of lymph nodes by serial sectioning and immunohistochemical techniques.
R12
In these patients, due to the risk of additional metastases in non-SLNs, an ALND as
R13
a second operative procedure is considered necessary for two reasons: locoregional
R14
control of the axilla and the possibility that additional metastastic lymph nodes may
R15
influence subsequent non-surgical therapy.
R16
R17 In a prospective cohort of breast cancer patients staged by SLNB and with the routine
R18
use of intraoperative use of FS analysis we assessed the proportion of patients in whom
R19
intraoperative FS analysis revealed no metastases while the definitive pathology
R20
examination did detect metastases. In these patients, the clinical implications of a
R21
“postponed” ALND were evaluated.
R22
R23
Patients and Methods
R24
R25 Between November 2000 and May 2008, data were collected prospectively regarding
R26
1004 consecutive patients who underwent surgical treatment using SLNB as a staging
R27
procedure for clinically staged T1-2N0 breast cancer. For the present study, patients
R28
were selected that underwent FS analysis of axillary SLNs.
R29
R30 The study group consisted of 879 patients since 125 patients did not undergo FS
R31
analysis and were therefore excluded from further analysis. Reasons for not
R32
R33
R34 Frozen section analysis of sentinel lymph nodes | 27
R1
performing FS analysis of SLNs were: small size of the SLNs, i.e. when the pathologists
R2
deemed the SLNs to small or to fatty for reliable FS analysis (n = 64), the introduction
R3
of this new staging technique when SLNB was followed by ALND on a routine basis
R4
(n = 30), clinical trial participation obviating ALND (assignment to the radiotherapy-
R5
arm of the AMAROS-trial, n = 26)5 or inability to retrieve a visualized axillary SLN
R6
(n = 5; the surgical success rate of SLN retrieval was 99.4%).
R7 R8
For the SLNB a one-day protocol was used. The visualization and identification of SLNs
R9
consisted of preoperative lymphoscintigraphy and the intraoperative use of a g-ray
R10
detection probe together with patent blue dye (Bleu patenté V, Laboratoire Guerbet,
R11
Aulnay-sous-Bois, France). Injections were given peritumorally and subcutaneously
R12
directly above the tumor. In nonpalpable breast tumors injections were guided by
R13
using an ultrasound probe or a radiologically placed wire. Imaging was done directly
R14
after the nanocolloid injection and two hours later. In the afternoon of the same
R15
day patients were operated. Axillary SLNs were retrieved first and send for FS
R16
analysis. Subsequently, internal mammary (IM) SLNs were collected when visualized
R17
on preoperative lymphoscintigraphy. These IM SLNs were not sent for FS analysis.
R18
Detailed information about this procedure was published previously6.
R19
R20
In the pathology department the SLNs were isolated from fatty tissue, bisected
R21
longitudinally, separately formalin-fixed, paraffin embedded, and frozen in liquid
R22
nitrogen. The first complete cut from both halves was stained with haematoxylin
R23
and eosin (H&E) and examined for the presence of metastases by the pathologist.
R24
The result of the FS analysis was reported to the operating surgeon with a median of
R25
22 minutes after removal of the axillary SLNs and usually before the surgery for the
R26
primary breast tumor was completed. If FS confirmed the presence of metastases in
R27
the SLN, an ALND was done. An ALND consisted of the removal of all axillary fat from
R28
levels I and II and as much as from level III as could be obtained through the axillary
R29
incision.
R30
R31
Postoperatively, the remaining tissue of the axillary SLNs, and IM SLNs were fixated
R32
in formalin and embedded in paraffin. The presence of lymph node metastases was
R33
R34 28 | Chapter 3
investigated by examining five cuts from both halves of the node, 250 μm apart,
R1
with H&E- and immunohistochemical techniques staining for cytokeratin-8 (IHC).
R2
The examining pathologist assessed tumor diameter, the modified Bloom Richardson
R3
grade (BR-grade)7, Mitotic Activity Index (MAI), hormonal receptor status (estrogen
R4
receptor (ER) and progesterone receptor (PR)) for all patients and Her2/neu status
R5
from 2004 on. The presence of lymph node metastases was classified according to
R6
the 2002 version of the UICC-TNM-classification8.
R7
When the intraoperative FS did not show metastases but the definitive histology did
3
R8 R9
reveal lymph node metastases, patients were advised to undergo a second operation
R10
to perform a complementary ALND. Lymph nodes from the complementary ALND-
R11
specimen were fixated in formalin, embedded in paraffin, and two cuts from the
R12
centre of the node were examined after staining with H&E and IHC.
R13
The indication for subsequent non-surgical treatment was determined applying the
R14
Dutch national guidelines (2008, version 1.1)9. In summary:
R15
•
• •
Adjuvant systemic chemotherapy is advocated in patients younger than 70
R16
years and in the presence of lymph node (macro) metastases, or when the
R17
tumor diameter exceeds 2 cm, or when the tumor is larger than 1 cm and
R18
the BR-grade is II or III.
R19
Adjuvant hormonal therapy is advocated under similar conditions, given ER-
R20
positive status of the tumor, but irrespective of age.
R21
Radiotherapy other than as part of breast conserving therapy and
R22
irrespective of tumor size is indicated when ≥ 4 axillary lymph nodes or level
R23
III axillary lymph nodes contain metastases. Locoregional radiotherapy is
R24
then advocated. When IM SLNs contain metastases (and axillary SLNs not)
R25
radiotherapy of the parasternal and midclavicular field is indicated.
R26
R27 Follow-up started at the date of the first operative procedure. Dates of death and
R28
locoregional recurrence were recorded prospectively until the last patient visit
R29
between October 2007 and May 2008.
R30
R31
R32
R33
R34 Frozen section analysis of sentinel lymph nodes | 29
R1
The frequency of a “positive” FS result, i.e. SLN metastases present, and the frequency
R2
of discordance between the intraoperative FS result “no metastasis” and the finding
R3
of lymph node metastases in the formalin fixated and cytokeratin stained additional
R4
cuts of the SLN were assessed. The metastatic burden in the two groups, reflected in
R5
the respective TNM N-classes was compared by using Chi-square analysis.
R6
Then, for patients who underwent a postponed ALND after a discordant FS result the
R7
proportion of patients with additional lymph node metastases was analyzed as well
R8
as the proportion of these latter patients with an increased TNM-N class. The advice
R9
for subsequent non-surgical treatment was determined after the first operation and
R10
again after the postponed ALND, and we evaluated how often the complementary
R11
ALND led to adjustment of non-surgical treatment.
R12
Lastly, we compared cumulative overall survival and the occurrence of locoregional
R13
relapses for the three groups delineated by the FS and the definitive pathology
R14
examination result.
R15
R16
Results
R17
R18
The median age of the 879 patients was 60 years (range 24 - 92), the clinicopathologic
R19
characteristics are summarized in table 1. In addition to the axillary SLNs that were
R20
removed in all patients inherent to the selection of patients, IM SLNs were visualized
R21
on the preoperative lymphoscintigraphy in 193 patients. These IM SLNs were
R22
successfully removed in 157 (81%) of the patients.
R23
Axillary lymph node metastases were detected in 359 patients: in the SLN by
R24
intraoperative FS (n = 200), in the SLN after the definitive pathology examination
R25
(discordant FS result; n = 151), in an axillary, non-SLN, not examined by FS (n = 4), or
R26
within the removed breast tissue, i.e. intramammary (n = 4). Also, 42 patients had
R27
IM lymph node metastases (27%), usually in combination with axillary metastases.
R28
Isolated IM metastases were found in nine patients. A total of 511 patients (58%) had
R29
no lymph node metastases.
R30
R31
R32
R33
R34 30 | Chapter 3
Table 1: Clinicopathologic characteristics of the patients Characteristic Patients (n) Age (years): median (range) Tumor size (cm) 3 Unknown Definitive nodal status N0 Nitc N1micro N1a N1b N1c N2a N3a N3b
R3
59.6 (24.2-92.1)
R4
106 (12.1) 461 (52.4) 231 (26.3) 74 (8.4) 7 (0.8)
R5
368 (41.9) 337 (38.3) 164 (18.7) 10 (1.1)
Oestrogen receptor status Positive Negative Unknown Progesterone receptor status Positive Negative Unknown Her2/neu status Positive Negative Unknown1 Histopathologic type Ductal Lobular Tubular Other Unknown 1
R2
879 (100)
511 (58.1) 24 (2.7) 95 (10.8) 158 (18.0) 9 (1.0) 20 (2.3) 38 (4.3) 17 (1.9) 7 (0.8)
Bloom-Richardson grade Well differentiated Moderately differentiated Poorly differentiated Unknown
R1
No. (%)
759 (86.3) 119 (13.5) 1 (0)
R6 R7
3
R8 R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
584 (66) 293 (34) 2 (0.1)
R22
75 (8.5) 667 (75.9) 137 (15.6)
R25
744 (84.6) 108 (12.3) 9 (1.0) 14 (1.6) 4 (0.5)
Before 2004 Her2-neu status was not routinely analyzed.
R23
R24
R26
R27
R28
R29
R30
R31
R32
R33
R34 Frozen section analysis of sentinel lymph nodes | 31
R1 R2
Intraoperative FS analysis detected axillary metastases in 200 patients (23%; figure
R3
1). In these patients, a direct complementary ALND revealed additional metastases
R4
in 101 patients (51%). Definitive lymph node status was classified as: N1micro (n = 10),
R5
N1 (n = 133), ≥ N2/N3 (n = 57; table 2).
R6 R7 R8 R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
R31
R32
R33
R34
Breast cancer surgery and SLNB n = 1004 No FS analysis n = 125 FS analysis of axillary SLN n = 879 FS: metastases + n = 200 FS: metastases − n = 679 FS − / definitive PA: metastases − n = 528* FS − / definitive PA: metastases + n =151 complementary ALND n = 112 Figure 1: Flowchart of the patients. SLNB: sentinel lymph node biopsy, FS: frozen section, PA: pathology result, ALND: axillary lymph node dissection. * 17 patients had regional lymph node metastases. 32 | Chapter 3
In 151 patients the FS result was discordant with the result of the definitive pathology
R1
examination: axillary lymph node metastases were found only after the definitive
R2
examination of the serial sectioned lymph nodes (17%). A second operation in
R3
order to perform a complementary ALND was not done in 39 of them (26%) for
R4
various reasons: age or frailty of the patient (n = 25), an already existing indication
R5
for parasternal radiotherapy due to metastases in IM SLNs (n = 5), a synchronous
R6
contralateral breast cancer with preoperatively proven lymph node metastases (n =
R7
3
2), or unknown (n = 7).
R8 R9
In the 112 patients who underwent ALND as a secondary operation due to discordance
R10
between FS and definitive pathology examination of the SLN, the pathological
R11
findings of the ALND specimen revealed additional lymph node metastases in 17
R12
patients (15%). In comparison to the group of patients with “positive” FS results, the
R13
metastatic burden in the regional lymph nodes was significantly less in the group
R14
with discordant FS results (P < 0.001; table 2).
R15
R16 Table 2. Metastatic lymph node involvement (UICC-TNM N classes) in relation to the detection of metastases by frozen section analysis or after definitive pathology examination of the sentinel lymph node FS: metastases + N-stage Nitc N1micro N1a N1c N2a N3a N3b
(n = 200*) 10 (5) 122 (61) 11 (6) 33 (17) 17 (9) 7 (4)
FS- / metastases definitive PA: metastases + (n = 151*) 24 (16) 84 (56) 31 (21) 8 (5) 4 (3) -
P** < 0.001
Values in parentheses are percentages. Definitive N-status as determined after definitive surgery, including the findings in the IM SLNs. *3 patients in the FS + group and 39 patients in the other group did not have an ALND, N-class was based on the examination of the SLN(s); see text results. **Chi-square analysis FS: frozen section SLN: sentinel lymph node
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
R31
R32
R33
R34 Frozen section analysis of sentinel lymph nodes | 33
R1
The finding of additional lymph node metastases in 17 patients resulted in a
R2
higher UICC-TNM-N-class in seven patients (6%; table 3). When applying the Dutch
R3
national guidelines, the findings of the subsequent ALND resulted in adjustment of
R4
subsequent non-surgical treatment in four patients (4%). These four patients were
R5
advised to receive more extensive locoregional radiotherapy. No patient would have
R6
received additional hormonal- and/or chemotherapy based on the complementary
R7
ALND (table 4).
R8 R9
After a median follow-up of 40 months the estimated cumulative 5-years overall
R10
survival was 90% in the group of patients with a discordant FS result, compared to
R11
94% in the group who had no axillary metastases and 80% in the group who had
R12
metastases that were detected by FS analysis (P < 0.001; logrank test). At the end of
R13
follow-up locoregional relapses had been detected in one (0.7%), four (0.8%) and six
R14
patients (3%) respectively. None of the 39 patients who had metastases in the SLN
R15
but did not undergo a postponed ALND developed an axillary relapse.
R16
R17
R18
R19
R20
R21
Table 3. N-class adjustment as the result of complementary ALND in patients with discordant FS results of SLNs (n = 7) Tumor Diameter Tumor Extra tumor efinitive N-class after 1st Patient positive of axillary positive positive LNs N-class after (nr.) axillary metastasis surgery IM SLNs (n) after ALND ALND SLNs (n) (mm) 1
2
1.1
0
N1micro
+1
N1micro → N1a
2
1
0.7
0
N1micro
+1
N1micro → N1a
3
1
1.3
0
N1micro
+2
N1micro → N1a
R25
4
1
>2
0
N1a
+5
N1a → N2a
R26
5
2
>2
0
N1a
+3
N1a → N2a
R27
6
1
3.5
0
N1a
+3
N1a → N2a
R28
7
2
>2
0
N1a
+2
N1a → N2a
R22
R23
R24
R29
R30
SLNs: sentinel lymph nodes, ALND: axillary lymph node dissection, LNs: lymph nodes, IM: internal mammary chain
R31
R32
R33
R34 34 | Chapter 3
Frozen section analysis of sentinel lymph nodes | 35
49
75
46
57
62
43
77
Age (yrs)
N1a → N2a
N1a → N2a
N1a → N2a
N1a → N2a
N1micro → N1a
N1micro → N1a
N1micro → N1a
Definitive N-stage after ALND
2.1
1.1
2.2
2.1
6
2.3
4.8
-
-
-
U*
-
-
-
Tumor size Her2/neu (cm)
+/+
+/+
+/-
+/-
+/+
-/-
-/-
ER/ PR
1
2
1
1
1
2
3
BRgrade
prot.
no
no
no
prot.
loco
no
RT
yes
no
yes
yes
yes
yes
no
CT (y / n)
yes
yes
yes
yes
yes
no
no
HT (y / n)
Proposed post-surgical treatment after first operation (SNLB and FS)
Yes, loco RT
Yes, loco RT
Yes, loco RT
Yes, loco RT
No
No
No
Treatment adjustment?
Definitive treatment after second operation (ALND)
SLNB: sentinel lymph node biopsy, FS: frozen section, ALND: axillary lymph node dissection, RT: radiotherapy: locoregional, according to protocol, CT: chemotherapy, HT: hormonal therapy, BR-grade: Bloom-Richardson grade, ER/PR: estrogen- progesterone receptor status. *Unknown
7
6
5
4
3
2
1
Patient (nr.)
Tumor characteristics
Table 4. Adjustment of subsequent non-surgical treatment in patients with a higher N-class after the complementary ALND following discordant FS results of SLNs (n = 7)
R1
R2
R3
R4
R5
R6
R7
3 R8
R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
R31
R32
R33
R34
R1
Discussion
R2 R3
In this prospective cohort of breast cancer patients discrepancy between “negative”
R4
FS analysis and the definitive pathology examination of SLNs was common,
R5
occurring in 17% of all patients and in almost half of the patients with lymph node
R6
metastases. In this selection of patients, an ALND as a secondary operation revealed
R7
additional metastases in 17% of the patients, influencing subsequent radiotherapy
R8
in a small proportion of patients. Adjuvant systemic treatment (hormonal- and/or
R9
chemotherapy) was not adjusted.
R10
R11
The present study describes a large cohort of consecutive breast cancer patients
R12
operated since the introduction of the SLNB in our hospital. Despite the volume
R13
of the overall group, the cohort of interest (i.e. the selection of 151 patients with
R14
discordant FS results in whom ALND as a second operation was indicated) was still
R15
modest. In addition, limiting the study group and introducing a potential source of
R16
selection bias, a substantial number of patients had no complementary ALND after
R17
the discordant FS result.
R18
R19
Discordance between FS analysis and the definitive pathology result was common,
R20
occurring in 17% of the patients operated for cT1-2N0 breast cancer. In itself, this is not
R21
surprising since serial sectioning will reveal the smaller metastases that go unnoticed
R22
when examining two cuts from the centre of a lymph node when intraoperative
R23
FS analysis is done. As one would expect, discrepancy between FS and definitive
R24
pathology examination was strongly related to minimal lymph node involvement3,10-12.
R25
Apparently, FS analysis can discriminate reliably between gross and limited (or no)
R26
metastatic lymph node involvement.
R27
R28
Many studies have addressed the chances of additional non-SLN lymph node
R29
metastases in patients with micrometastases in SLNs. Since most of the patients with
R30
discordance between the FS and definitive pathology result had micrometastases in
R31
their SLNs, the observed frequency of additional metastases following the postponed
R32
ALND is unsurprisingly similar to the reported proportions of non-SLN metastases
R33
R34 36 | Chapter 3
in patients with SLNs with micrometastases3,4. Observing additional metastases in
R1
approximately 15% of the patients who underwent a postponed ALND, most authors
R2
underline the importance of a complementary ALND4,13.
R3
No studies, to our knowledge, investigated the clinical consequences of the ALND in
R4
the selection of patients who had discordant FS results. In this selection of patients
R5
the metastatic lymph node involvement is limited and remains so after the postponed
R6
ALND. While additional metastases were quite common, extra adjuvant systemic
R7
treatment was never advised, while more extensive (locoregional) radiotherapy was proposed in less than five % of the patients. These very limited clinical implications
3
R8 R9
of the postponed ALND were surprising. Then again, recent data suggest that even
R10
limited lymph node involvement has an adverse prognostic effect on outcome, and
R11
the authors advocate adjuvant systemic therapy in all patients with micrometastases
R12
and isolated tumor cells14 . In that perspective, a postponed ALND would by definition
R13
have no effect on systemic therapy.
R14
In contrast to the limited implications of the ALND after a discordant FS result, extensive
R15
metastastic lymph node involvement, that is, TNM-class N2 or N3, was found in more
R16
than one quarter of the patients when FS analysis revealed lymph node metastases
R17
intraoperatively and ALND was done instantly. This necessitated extension of the
R18
radiotherapy-field and potentially led to more intensive chemotherapy in a similar
R19
proportion.
R20
R21 The primary objective of intraoperative FS analysis of axillary SLNs is sparing patients
R22
a second operative procedure. In addition, the present data demonstrate that when
R23
there is discrepancy between a negative FS analysis and a tumor-positive definitive
R24
pathology result, the ALND is merely advised for locoregional control decreasing
R25
the risk of axillary recurrence in the future by removing additional metastases in
R26
non-SLNs in a substantial proportion of patients and by necessitating extension of
R27
the radiotherapy treatment in a small proportion of patients. However, ALND as a
R28
procedure to improve locoregional control, has been under debate well before the
R29
era of the SLNB procedure. This makes the case for routine ALND in this category of
R30
patients with very limited metastatic lymph node involvement, questionable .
R31
15
R32
R33
R34 Frozen section analysis of sentinel lymph nodes | 37
R1
Radiotherapy of the axilla is currently under investigation in a randomized trial (EORTC-
R2
trial 10981 - AMAROS-trial), evaluating the role of radiotherapy as a substitute for
R3
ALND in patients with metastases-containing SLNs5. If this trial will document similar
R4
locoregional control rates, radiotherapy will be a proper alternative for axillary
R5
treatment that will probably be preferred by many women and clinicians. In patients
R6
with gross metastatic lymph node involvement ALND may still be desirable to obtain
R7
optimal staging information that will influence non-surgical treatment in a quarter
R8
of the patients. When metastases are only detected by the definitive pathology
R9
examination, ALND will very rarely lead to post-surgical treatment changes. These
R10
latter patients will be very good candidates for radiotherapy to the axilla obviating
R11
the need for a postponed ALND.
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
R31
R32
R33
R34 38 | Chapter 3
References
R1 R2
1.
2.
3.
Giuliano AE, Dale PS, Turner RR, et al. Improved axillary staging of breast cancer with sentinel
R3
lymphadenectomy. Ann Surg 1995;3:394-401
R4
Miltenburg DM, Miller C, Karamlou TB, Brunicardi FC. Meta-analysis of sentinel lymph node biopsy
R5
in breast cancer. J Surg Res 1999;84:138-142
R6
Wada N, Imoto S, Hasebe T, Ochiai A, Ebihara S, Moriyama N. Evaluation of intraoperative frozen
R7
section diagnosis of sentinel lymph nodes in breast cancer. Jpn J Clin Oncol 2004;34:113-117 4.
Cserni G, Gregori D, Merletti F, et al. Meta-analysis of non-sentinel node metastases associated with
3
R8 R9
micrometastatic sentinel nodes in breast cancer. Br J Surg 2004;91:1245-1252
R10
5.
EORTC- Amaros trial 10981: After mapping of the axilla: radiotherapy or surgery?
R11
6.
Madsen EVE, Gobardhan PD, Bongers V, et al. The impact on post-surgical treatment of sentinel
R12
lymph node biopsy of internal mammary lymph nodes in patients with breast cancer. Ann Surg
R13
Oncol 2007;14:1486-1496
R14
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. The value of histological grade in
R15
breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19:403-
R16
410
R17
Sobin ELH. and Wittekind Ch. UICC TNM classification of malignant tumours. New York: Wiley-Liss;
R18
2002
R19
Dutch National Guideline Breast Carcinoma, Sep 2008; version 1.1. http://www.oncoline.nl
R20
7.
8.
9.
10. Grabau DA, Frank F, Friis E. Intraoperative frozen section examination of axillary sentinel lymph
R21
R22
nodes in breast cancer. APMIS 2005;113:7-12 11. Chao C, Wong SL, Ackermann D, Simpson, et al. Utility of Intraoperative frozen section analysis of sentinel lymph nodes in breast cancer. Am J Surg 2001;182:609-615
R23
R24
12. Weiser MR, Montgomery LL, Susnik B, Tan LK, Borgen PI, Cody HS. Is routine intraoperative
R25
frozen-section examination of sentinel lymph nodes in breast cancer worthwile? Ann Surg Oncol
R26
2000;7:651-655
R27
13. Christiansen P, Friis E, Balslev E, Jensen D, Møller S. Sentinel node biopsy in breast cancer: Five years experience from Denmark. Acta Oncologica 2008;47:561-568 14. de Boer M, van Deurzen CH, van Dijck JA, Borm GF, van Diest PJ, et al. Micrometastases or isolated tumor cells and outcome of breast cancer. New Engl J Med. 2009;361:653-663
R28
R29
R30
R31
R32
R33
R34 Frozen section analysis of sentinel lymph nodes | 39
R1
15. Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology Guideline
R2
Recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol
R3
2005;23:7703-7720
R4 R5 R6 R7 R8 R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
R31
R32
R33
R34 40 | Chapter 3
4 Axillary reverse mapping (ARM): the need for selection of patients Paul D. Gobardhan Jan H. Wijsman Thijs van Dalen Elisabeth G. Klompenhouwer George P. van der Schelling Jan Los Adri C. Voogd Ernest J.T. Luiten Department of Surgery, Amphia Hospital Breda Department of Surgery, Diakonessenhuis Utrecht/Zeist Department of Pathology, Amphia Hospital Breda Comprehensive Cancer Centre South, Eindhoven Cancer Registry
Submitted
R1
Abstract
R2 R3
Background: Axillary reverse mapping (ARM) is a technique that discerns axillary
R4
lymphatic drainage of the arm from the breast. This study was performed to evaluate
R5
both the feasibility of this technique and the proportion of metastatic involvement
R6
of ARM-nodes.
R7 R8
Patients and Methods: Patients with invasive breast cancer and an indication for
R9
axillary lymph node dissection (ALND) were enrolled in the study: patients with a
R10
tumor-positive sentinel lymph node (SLN+-group) and patients who had axillary
R11
metastases proven by preoperative cytology (CP-N+-group) were distinguished. ARM
R12
was performed in all patients by injecting blue dye. During surgery ARM-nodes were
R13
identified and removed first, followed by ALND.
R14
R15
Results: Between October 2009 and June 2011 93 patients underwent ARM.
R16
There were 43 patients in the SLN+-group and 50 patients in the CP-N+-group. No
R17
significant differences in visualization rate of ARM-nodes between the groups (86
R18
vs 94% respectively, P = 0.196) were identified. In the SLN+-group none of the ARM-
R19
nodes contained metastases versus 11 patients (22%) in the CP-N+-group (P = 0.001).
R20
Patients receiving neoadjuvant systemic therapy had a significantly lower risk of
R21
additional axillary lymph node metastases (24.6 vs 44.4%, P = 0.046).
R22
R23
Conclusion: The ARM procedure is technically feasible with a high visualization rate.
R24
The proportion of patients with metastases in the ARM-nodes was significantly
R25
higher in patients with proven axillary metastases than in patients with a positive SLN.
R26
Patients with SLN metastases appear to be good candidates for the ARM technique
R27
and possibly also patients with proven axillary metastases receiving neoadjuvant
R28
chemotherapy.
R29
R30
R31
R32
R33
R34 42 | Chapter 4
Introduction
R1 R2
Sentinel lymph node biopsy (SLNB) is standard of care for lymph node staging in breast
R3
cancer patients who are clinically node negative (cN0). It avoids routine axillary lymph
R4
node dissection (ALND) in the majority of patients1. Although recently published data
R5
of the Z0011 trial cast doubt on the necessity of ALND in patients with sentinel lymph
R6
node (SLN) metastases2, ALND is still indicated in a substantial proportion of patients.
R7
Axillary reverse mapping (ARM) is a recently described technique which enables
R8
discrimination of lymphatic drainage of the breast from the arm. This technique
R9
involves the use of either blue dye, fluorescence or a radioisotope to visualize upper
R10
extremity lymph nodes and lymphatics. In the past few years a number of studies
R11
have been published regarding this relatively new technique
. In some of these,
3-10
ARM was done concurrently with SLNB7,9,10 showing that ARM nodes and SLNs
4
R12
R13
draining the breast in some cases are the same lymph node. Others reported on
R14
performing ARM during ALND in patients with proven SLN metastases5,6,8.
R15
In the present cohort study, using blue dye only, ARM was performed in patients
R16
who underwent ALND for previously proven lymph node metastases, as determined
R17
by SLNB or preoperative cytology. Visualization and metastatic involvement rates
R18
were compared for patients who had metastases in SLNs and patients who had
R19
cytologically proven lymph node metastases.
R20
R21
Patients and Methods
R22
R23 Study cohort
R24
Between October 2009 and July 2011 93 patients diagnosed with invasive breast
R25
cancer who were advised to undergo an ALND were enrolled in the study. The
R26
indication for ALND was a SLN containing metastases (> 0.2 mm) or lymph node
R27
metastases proven by preoperative cytology.
R28
Demographic data, information about the operative procedure, treatment with
R29
neoadjuvant systemic therapy after the SLNB but before definitive axillary surgery and
R30
the pathology results were collected prospectively. The medical ethical committee of
R31
the hospital approved the routine use of the SLNB as a staging procedure and the use
R32
R33
R34 Axillary reverse mapping | 43
R1
of ARM for this study. All patients received information regarding the SLNB, ALND
R2
and ARM procedure.
R3 R4
Blue dye injection and surgery
R5
In all patients blue dye (Bleu patenté V, Laboratoire Guerbet, Aulnay-sous-Bois,
R6
France) was injected in the ipsilateral upper extremity. Following a subcutaneus
R7
injection of approximately 2.0 cc in the medial bicipital sulcus between m. biceps
R8
brachii and m. triceps brachii, the injection site was massaged gently for five minutes.
R9
This procedure was performed just a few minutes before the start of the operation.
R10
During surgery ARM lymph nodes and lymphatics were identified first and the lymph
R11
nodes removed separately. A standard ALND (at least level I-II) was performed
R12
subsequently. No attempts were made to spare upper extremity lymphatics, as this
R13
was not the goal of this study. All lymph nodes were formaline fixed and sent for
R14
pathological examination.
R15
R16
(Neo)adjuvant chemotherapy
R17
In the majority of the patients (neo)adjuvant systemic therapy was indicated. In our
R18
institute there is a policy towards liberal use of neoadjuvant chemotherapy (NAC).
R19
Treatment with NAC was discussed with the patient if the indication for chemotherapy
R20
already existed before surgery was performed (e.g. cytology proven positive axillary
R21
lymph node, large tumor size, high malignancy grade and/or young age). Clinically
R22
node negative patients indicated for neoadjuvant chemotherapy underwent a SLNB
R23
prior to the start of the chemotherapy to determine the axillary lymph node status.
R24
R25
Pathological examination
R26
Primary tumor diameter, malignancy grade applying the modified Bloom and
R27
Richardson (BR) grade11, estrogen- (ER) and progesteron (PR) –receptorstatus and
R28
Her2/neu status were assessed. In accordance with the national pathology protocol12,
R29
all retrieved axillary lymph nodes (including the ARM-nodes) were embedded in
R30
paraffin and two central cuts from every lymph node were examined after staining
R31
with haematoxylin and eosine (H&E) and immunohistochemically (IHC) with an
R32
antibody against keratin.
R33
R34 44 | Chapter 4
Classification of patients
R1
Patients were classified and divided into two groups according to their primary
R2
clinical axillary status. The first group (SLN+) consisted of patients with micro- or
R3
macrometastatic lymph node involvement in the SLN who were advised to undergo
R4
a complementary ALND. The second group (CP-N+) consisted of patients who had a
R5
preoperative (cytological) diagnosis of lymph node metastases and were scheduled
R6
for ALND. Intraoperative visualization/identification rates as well as the proportion
R7
of metastatically involved ARM and axillary nodes were evaluated for both groups.
R8
The number of additionally involved lymph nodes was defined as the number of
R9
metastatic lymph nodes in the axilla (axillary and ARM) other than the SLN itself in
R10
the SLN -group. In the CP-N+ group the number of additional axillary lymph nodes
R11
+
was defined as the overall number of metastastic nodes minus the one node that was proven to contain metastases (by cytological aspiration).
4
R12
R13
R14 Statistical analysis
R15
Statistical analyses were performed using SPSS, version 18.0 (SPSS, Inc., Chicago,
R16
USA). Chi-square analysis was performed to evaluate proportional differences
R17
between the two groups regarding visualization rates as well as regarding the
R18
proportion of patients with metastatic lymph node involvement. P values of ≤ 0.05
R19
were considered significant.
R20
R21
Results
R22
R23 The median age of the 93 patients was 56.4 years. There were 43 women (46.2%)
R24
in the SLN+-group and 50 (53.8%) in the CP-N+-group. Baseline characteristics of
R25
both groups are shown in table 1. Notably, women in the CP-N+-group had larger
R26
tumors and were more likely to have poorly differentiated, ER-negative, PR-negative
R27
and Her2/neu-positive tumors. Neoadjuvant chemotherapy was significantly more
R28
often prescribed in the CP-N -group compared to the SLN -group (76.0% and 44.2%
R29
respectively, P = 0.002)
R30
Overall ARM-nodes could be visualized in 84 (90.3%) patients. There were no
R31
differences in the visualization rate between the two groups (86.0% for SLN+ and
R32
94.0% for CP-N+, P = 0.196).
R33
+
+
R34 Axillary reverse mapping | 45
Table 1. Baseline characteristics for 93 breast cancer patients
R1 R2
Characteristic
R3 R4
Age (years)a
R5 R6
Tumor size (cm)b,*
R7
Tumor size (%)* < 1cm 1-2 cm 2-3 cm > 3 cm Bloom-Richardson grade (%) Well differentiated Moderately differentiated Poorly differentiated Unknown** Estrogen Receptor positive (%) Progesterone Receptor positive (%) Her2/neu Receptor positive (%) Additional lymph nodes involved at ALND (%) 0 1 2-3 >3
R8 R9
R10
R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
Total n = 93 56.4 (+/- 12.1) 3.0 (0.39-12.0)
Neoadjuvant systemic treatment (%)
SLN+ and CP-N+ CP+ SLN+ n = 43 n = 50 56.5 56.4 (+/-13.9) (+/-10.4) 2.8 3.5 (0.39-8.0) (0.40-12.0)
P 0.964c 0.106d
7 (7.5) 21 (22.6) 21 (22.6) 44 (47.3)
5 (11.6) 14 (32.6) 7 (16.3) 17 (39.5)
2 (4.0) 7 (14.0) 14 (28.0) 27 (54.0)
0.052e
19 (20.4 34 (36.6) 20 (21.5) 20 (21.5) 71 (76.3) 53 (57.0) 22 (23.7)
12 (27.9) 23 (53.5) 6 (14.0) 2 (4.7) 38 (88.4) 30 (69.8) 5 (11.6)
7 (14.0) 11 (22.0) 14 (28.0) 18 (36.0) 33 (66.0) 23 (46.0) 17 (34.0)
ChiSq
R2 R3
Age
0.943
0.902
0.984
0.007
R4
Radiotherapy breast
0.228
0.074
0.697
0.010
R5
Hormonal therapy
2.798
0.961
8.14
0.059
R6 R7 R8
Prognosis of patients with ipsilateral axillary recurrence
R9
At the time of detection of the regional recurrence all patients were re-staged. Three
R10
patients had synchronous bone metastasis and one patient had synchronous liver
R11
metastasis. The median follow-up post-recurrence was 29 months (range 0-58).
R12
R13
Discussion The present study was conducted to identify factors predictive for developing an
5
R14
R15
R16
axillary recurrence in SLN-negative breast cancer patients. Although many authors
R17
have reported the follow up results of SLN-negative patients, none have been able to
R18
determine factors predictive for developing an axillary recurrence. This is due to the
R19
low incidence of axillary recurrences. While the results of large randomized trials have
R20
to be awaited, two systematic reviews of the available literature have addressed the
R21
problem of axillary recurrences. One focused on the effect of different techniques of
R22
lymphatic mapping on the incidence of axillary recurrences. In this study the lowest
R23
recurrence rates were reported in studies performed in cancer centers, in studies
R24
that described the use of 99mTc-sulphur colloid and also when investigators used the
R25
superficial injection technique or evaluated the harvested SLN with H&E and IHC
R26
staining (P < 0.01) . Another review performed by our own group demonstrated that
R27
EBRT is associated with a significantly lower axillary recurrence rate after negative
R28
SLN . Both studies were limited in the fact that only variables mentioned in the
R29
original articles could be analyzed. For this reason no multivariable analysis testing
R30
for all patient-, tumor- and treatment characteristics could be performed.
R31
5
6
R32
R33
R34 Axillary recurrences after sentinel lymph node biopsy | 61
R1
The present study is unique in the fact that long term follow-up was available for
R2
a relatively large group of patients treated in different breast centers with uniform
R3
guidelines concerning initial and adjuvant treatment and follow up. Only one study
R4
has reported on more patients with an axillary recurrence after negative SLN but in
R5
that report no prognostic factors were mentioned1.
R6
A clear limitation of this study is the fact that, although the data collection was
R7
performed prospectively, the final analysis was done retrospectively. Secondly, serial
R8
sectioning at time of initial SLN analysis was done at 250-500 µm, which may leave
R9
metastases undiagnosed that would have been detected when sectioning at 150 µm.
R10
In the present study we demonstrated that young age is an independent risk factor
R11
for developing an axillary recurrence. This is consistent with other studies in which
R12
young breast cancer patients had a worse relapse free survival and breast cancer
R13
specific mortality9,10.
R14
A second highly significant finding is that radiotherapy (as part of BCT) decreased the
R15
chance of developing an axillary recurrence. This is consistent with the observations
R16
that have previously been reported by our research group in a single center study
R17
and with the systematic review on this subject6,11. The observation that EBRT to the
R18
breast reduces the incidence of local- and breast recurrence in breast cancer patients
R19
has been described before12. Reports are available on the radiation exposure (dose
R20
and extent) of the axillary nodes in standard EBRT to the breast as part of BCT. In
R21
standard tangential radiotherapy, the opposing fields encompass the site of the SLN
R22
in 78-94% of the examined patients13,14. One study reports a mean 95% isodose line
R23
coverage of 55% to level I and II nodes15. In another study the median dose given
R24
to level I and II nodes is 38.58 Gy and 20.65 Gy respectively16. Average percentages
R25
of prescribed dose could be as high as 66% in level I, 44% in level II and 31% in
R26
level III nodes17. Although it may not be considered a therapeutic dose, the dose
R27
delivered to the region in which the SLNs are normally found could well be enough
R28
to influence the natural evolution of tumor cells left behind. The low incidence of
R29
axillary recurrences (1.6% in the present study with a 5 year estimate for recurrence
R30
of 0.22%) is an insufficient argument to recommend locoregional irradiation of breast
R31
cancer patients treated with mastectomy. When regarding the evidence suggesting
R32
that ALND can safely be omitted in case of tumor positive SLN3, the current study
R33
R34 62 | Chapter 5
clearly identifies two specific groups of patients in whom one should be hesitant to
R1
withhold additional axillary treatment.
R2
The effect of systemic therapy on both survival and recurrence rates has been
R3
extensively investigated. An overview of randomized trials performed by the Early
R4
Breast Cancer Trialists’ Collaborative Group in 2005 showed that both hormonal-
R5
and chemotherapy have a positive effect on recurrence rate and 15-year survival18.
R6
The present study however did not show an independent effect of hormonal- and
R7
chemotherapy in developing an axillary recurrence.
R8
The effect of an axillary recurrence on overall survival remains unclear. Although a
R9
substantial number of patients had metastases at the time of axillary recurrence, no
R10
survival differences between N0, N1micro, Nitc and patients with N0(axillary recurrence) were
R11
found when measured from the time of the primary operation. A larger group of
R12
axillary recurrence patients should be analyzed to investigate the possible effect of
R13
an axillary recurrence on overall survival.
R14
In conclusion, even after long term follow up, the risk of developing an axillary recurrence is very low. Young age and the absence of radiation therapy are highly
5
R15
R16
significant risk factors for developing an axillary recurrence after a negative SLN for
R17
breast cancer. Future studies should investigate the effect an axillary recurrence on
R18
overall survival.
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
R31
R32
R33
R34 Axillary recurrences after sentinel lymph node biopsy | 63
R1
References
R2 R3
1.
R4 R5
Veronesi U, Viale G, Paganelli G, et al. Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study. Ann Surg 2010;251:595-600
2.
Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional
R6
axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall
R7
survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 2010;11:927-933
R8
3.
R9
invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011;305:569-
R10
R11
575 4.
R12
R13
Pepels MJ, Vestjens JH, de BM, et al. Safety of avoiding routine use of axillary dissection in early stage breast cancer: a systematic review. Breast Cancer Res Treat 2011;125:301-313
5.
R14
van der Ploeg IM, Nieweg OE, van Rijk MC, Valdes Olmos RA, Kroon BB. Axillary recurrence after a tumour-negative sentinel node biopsy in breast cancer patients: A systematic review and meta-
R15
R16
Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with
analysis of the literature. Eur J Surg Oncol 2008;34:1277-1284 6.
van Wely BJ, Teerenstra S, Schinagl DA, Aufenacker TJ, de Wilt JH, Strobbe LJ. Systematic review of
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the effect of external beam radiation therapy to the breast on axillary recurrence after negative
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sentinel lymph node biopsy. Br J Surg 2011;98:326-333
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7.
Wittekind C., Greene F.L., Hutter R.V.P., Klimpfinger M., Sobin L.H. Breast Tumours. TNM Atlas,
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illustrated guide to the TNM/pTNM Classification of Malignant Tumours. 5th edn. New York:
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Springer 2005.;p. 207-223
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8.
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Rutgers EJ, Nortier JW, Tuut MK, et al. [Dutch Institute for Healthcare Improvement guideline, “Treatment of breast cancer”]. Ned Tijdschr Geneeskd 2002;146:2144-2151
9.
Hanrahan EO, Valero V, Gonzalez-Angulo AM, Hortobagyi GN. Prognosis and management of patients
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with node-negative invasive breast carcinoma that is 1 cm or smaller in size (stage 1; T1a,bN0M0): a
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review of the literature. J Clin Oncol 2006;24:2113-2122
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10. Hanrahan EO, Gonzalez-Angulo AM, Giordano SH, et al. Overall survival and cause-specific mortality of patients with stage T1a,bN0M0 breast carcinoma. J Clin Oncol 2007;25:4952-4960 11. van Wely BJ, Smidt ML, de Kievit IM, Wauters CA, Strobbe LJ. False-negative sentinel lymph node biopsy. Br J Surg 2008;95:1352-1355 12. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004;351:963-970
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R34 64 | Chapter 5
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13. Chung MA, DiPetrillo T, Hernandez S, Masko G, Wazer D, Cady B. Treatment of the axilla by tangential
R2
breast radiotherapy in women with invasive breast cancer. Am J Surg 2002;184:401-402 14. Rabinovitch R, Ballonoff A, Newman F, Finlayson C. Evaluation of breast sentinel lymph node
R3
coverage by standard radiation therapy fields. Int J Radiat Oncol Biol Phys 2008;70:1468-1471
R4
15. Reed DR, Lindsley SK, Mann GN, et al. Axillary lymph node dose with tangential breast irradiation.
R5 R6
Int J Radiat Oncol Biol Phys 2005;61:358-364 16. Aristei C, Chionne F, Marsella AR, et al. Evaluation of level I and II axillary nodes included in the
R7
standard breast tangential fields and calculation of the administered dose: results of a prospective
R8
study. Int J Radiat Oncol Biol Phys 2001;51:69-73
R9
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17. Reznik J, Cicchetti MG, Degaspe B, Fitzgerald TJ. Analysis of axillary coverage during tangential
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radiation therapy to the breast. Int J Radiat Oncol Biol Phys 2005;61:163-168
R12
18. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year
R13
survival: an overview of the randomised trials. Lancet 2005;365:1687-1717
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R34 Axillary recurrences after sentinel lymph node biopsy | 65
6 Prognostic value of micrometastases in sentinel lymph nodes of patients with breast carcinoma: a cohort study Paul D. Gobardhan Sjoerd G. Elias Eva V.E. Madsen Vivian Bongers Hans J. Ruitenberg Cornelis I. Perre Thijs van Dalen Department of Surgery, Diakonessenhuis Utrecht Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht Department of Nuclear Medicine, Diakonessenhuis Utrecht Department of Pathology, Diakonessenhuis Utrecht Annals of Oncology, 2009;20:41-48
R1
Abstract
R2 R3
Introduction: The prognostic meaning and thus indication for adjuvant therapy
R4
of lymphogenic micrometastases in breast cancer patients is still under debate.
R5 R6
Patients and Methods: Between 1999 and 2007 703 patients with cT1-2N0 breast
R7
cancer underwent surgery including SLNB. Examination of SLNs consisted of H&E-
R8
and IHC staining following serial sectioning of the SLN. Patients were divided into
R9
four groups: N0 (n = 423), N1micro (n = 81), N1a (n = 130) and N≥1b (n = 69). Median
R10
follow-up was 40 months.
R11
R12
Results: At the end of follow-up 53 patients had died and 64 had recurrent disease.
R13
Compared to N0 and following adjustment for possible confounders, including
R14
adjuvant systemic treatment, overall survival was not significantly different for N1micro
R15
while significantly worse for N1a and N≥1b (HR [95% CI]: 0.59 [0.14-2.58]; 4.31 [1.85-
R16
10.01]; 10.66 [CI 4.04-28.14] respectively). Likewise, disease free survival was not
R17
significantly different for N1micro and worse for N1a and N≥1b (HR [95% CI]: 1.43 [0.67-
R18
3.02]; 2.79 [1.37-5.66]; 7.13 [3.27-15.54] respectively). Distant metastases were
R19
more commonly observed in the N1micro than in the N0 group, but still not as common
R20
as in the N1a or N≥1b group (HR [95% CI]: 4.85 [1.79-13.18]; 10.34 [3.82-28.00]; 23.25
R21
[7.88-68.56] respectively).
R22
R23
Conclusion: Although the risk of distant metastases was higher in patients with
R24
N1micro than in the N0 group, no statistically significant differences were observed in
R25
overall or disease free survival between N0 and N1micro. Micrometastatic lymph node
R26
involvement in itself should not be an indication for adjuvant chemotherapy in breast
R27
cancer patients.
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R34 68 | Chapter 6
Introduction
R1 R2
Axillary staging is a hallmark of breast cancer surgery as metastatic lymph node
R3
involvement is a strong prognosticator. The presence of lymphogenic metastases
R4
and number of involved lymph nodes contribute importantly to adjuvant systemic
R5
treatment decisions. In the era of the sentinel lymph node biopsy (SLNB), lymph nodes
R6
are assessed more thoroughly for tumor involvement than before. Consequently, the
R7
proportion of patients diagnosed with micrometastatic lymph node involvement (i.e.
R8
tumor deposits larger than 0.2 mm and smaller than two mm) has increased , and
R9
micrometastases are observed in up to 23% of breast cancer patients
R10
1-7
1,6,8
.
R11 These micrometastases pose a clinical dilemma with regard to adjuvant treatment
R12
decisions because their prognostic meaning is currently unclear. Most studies on
R13
this topic originate from the pre-SLNB era, are retrospective and yield inconsistent
R14
results. Some earlier reports suggested a prognosis of patients with TNM-stage N1micro
R15
disease comparable to patients without lymph node involvement (N0)9, while others
R16
observed a prognosis comparable to patients with TNM-stage N1a disease . In this
R17
10
study from the SLNB era, we evaluated the association between N1micro disease and clinical outcome compared to patients with N0, N1a and N≥1b disease.
6
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Patients and methods
R21
R22 Between June 1999 and January 2007, 720 consecutive patients with cT1-2N0 primary
R23
invasive breast cancer underwent surgical treatment including an SLNB procedure at
R24
the Diakonessenhuis Utrecht (a large regional teaching hospital in the Netherlands).
R25
These women were all enrolled in the current study. Data regarding demography,
R26
preoperative lymphoscintigraphy, operative procedure, pathology results and
R27
adjuvant treatment administration were collected prospectively. At the time of the
R28
introduction of the SLNB procedure the ethical committee of the hospital approved
R29
the routine use of the SLNB as a staging procedure. All patients received written
R30
information regarding the SLNB procedure.
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R34 Prognostic value of micrometastases: a cohort study | 69
R1
Patients who presented with a synchronous contralateral breast cancer (n = 8) or with
R2
multifocal carcinoma (n = 9) were excluded, to avoid difficulty of ascribing patient
R3
outcome to tumor-specific lymph node status. The cohort available for analysis
R4
consisted of 703 patients.
R5 R6
Sentinel lymph node procedure
R7
On the day of the operation, all patients received a combination of peritumoral
R8
intraparenchymal and subcutaneous injections of an average of 77.7 MBq (53-150
R9
MBq)
Tc nanocolloid. Continuous visualization was done and imaging started as
99m
R10
soon as lymphatic drainage was visualized on the persistence scope and at two to
R11
three hours after injection in both the anterior and lateral direction. The operative
R12
procedure was done in the afternoon of the same day. A γ-ray detection probe
R13
was intraoperatively used for sentinel lymph node (SLN) identification. During the
R14
operation both axillary and internal mammary (IM) sentinel nodes were retrieved.
R15
Axillary SLNs were visualized on lymphoscintigraphy, and collected by axillary
R16
exploration in 99% of the patients. IM SLNs were visualized in 22% of the patients,
R17
and in 78% of the patients with visualized IM SLNs they could be successfully retrieved
R18
through an intercostal exploration. Detailed information about this procedure was
R19
presented earlier by our study group11.
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Pathologic examination of the SLN
R22
Intraoperative frozen section analysis of the axillary SLNs was done to enable axillary
R23
lymph node dissection (ALND) during the same operative procedure in case of overt
R24
lymph node metastases. In addition, both axillary and IM SLNs were formalin-fixed,
R25
paraffin embedded and four cuts from both halves were taken at 250 µm intervals
R26
starting from the centre. The sections were stained both with haematoxylin and eosine
R27
(H&E) and immunohistochemically (IHC) with an antibody against keratin. When the
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axillary SLN contained metastases, a subsequent ALND was performed, either during
R29
the first operation when the frozen section analysis revealed metastases, or as a
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second operation, when the metastases were detected on the paraffin slices.
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R34 70 | Chapter 6
Classification of lymph node stage
R1
Based on the pathologic findings of the SLN and the axillary dissection specimens
R2
lymph node status was classified according to the 6th edition of the UICC-TNM-
R3
classification12.
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N0:
no regional lymph node metastasis
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Nitc :
clusters of tumor cells in regional lymph nodes less than 0.2 mm
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N1micro: metastasis in axillary lymph nodes with a size between 0.2 and 2.0 mm
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N1a:
1 to 3 axillary macrometastasis (at least one with size larger than 2.0 mm)
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N1b:
a single positive IM lymph node (diagnosed by SLNB, not clinically apparent)
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N1c:
a combination of N1a en N1b
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N2a:
4 to 9 ipsilateral axillary macrometastases
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N3a:
10 or more axillary macrometastases
R12
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According to the UICC-TNM Classification Nitc was classified as N0.
R15 Non-operative treatment
R16
Based on the axillary lymph node status and primary tumor characteristics, adjuvant
R17
systemic and/or radiotherapeutic treatment was given in accordance with the Dutch national guidelines . The finding of macrometastatic disease in the axillary lymph 13
6
R18
R19
nodes or IM lymph node metastases (TNM-stage N1a-c/N2/N3) were indications for
R20
adjuvant therapy. Furthermore, primary tumor size, hormonal receptor status (ER
R21
and PR), modified Bloom-Richardson (BR) malignancy grade (classified according to
R22
the Nottingham modification14) and patient age were taken into account.
R23
In patients with N1micro disease and favorable primary tumor characteristics, the
R24
guideline states that it is not clear whether the prognosis of TNM-stage N1micro
R25
justifies adjuvant systemic treatment13,15,16. The uncertain benefit of, and indication
R26
for, adjuvant systemic treatment was discussed with all patients by the medical
R27
oncologist and the choice to give hormonal- and/or chemotherapy was made by the
R28
physician and the patient.
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R34 Prognostic value of micrometastases: a cohort study | 71
R1
Follow-up
R2
Follow-up started at the date of first operation. Patients were routinely seen twice
R3
yearly during outpatient visits, and a mammography was made annually. Dates of
R4
subsequent locoregional recurrence, contralateral breast cancer, osseal or visceral
R5
metastasis and death were recorded prospectively until August 2007. General
R6
practitioners were actively contacted for additional information when patients had
R7
not visited the hospital for 12 months.
R8 R9
Analysis
R10
Several patients had co-variables with missing values: tumor size (n = 4), modified
R11
Bloom-Richardson grade (n = 5), Mitotic Activity Index (n = 14), Progesterone
R12
Receptor status (n = 1), Her2/neu status (n = 120), adjuvant radiotherapy (n = 3),
R13
adjuvant hormonal therapy (n = 22), and adjuvant chemotherapy (n = 22). As it has
R14
been shown that the analysis of data after omitting patients with a missing value
R15
reduces statistical power and often lead to a biased result, we used an imputation
R16
method to replace missing values17,18. This was done for all variables with missing data
R17
except for Her2/neu status, which was deemed to be missing in too many patients
R18
(17%; due to the relatively recent introduction of Her2/neu assessment in clinical
R19
practice). In total, 40 patients (6%) with missing data on one or more co-variables
R20
had these values imputed by an expectation-maximization method (Missing Value
R21
Analysis command, SPSS 14.0 [SPSS, Chicago, IL]). For this we used all co-variables
R22
and including information on outcome and lymph node status. All analyses that we
R23
report are based on this dataset with imputed values, but we also analyzed the data
R24
using a complete-case approach to evaluate the robustness of our findings.
R25
R26
Based on the metastatic involvement of regional lymph nodes patients were
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categorized into four groups for analysis: N0 (including Nitc), N1micro, N1a, and N≥1b.
R28
Then N0, N1micro, N1a and N≥1b groups were compared for differences in age, tumor
R29
characteristics and adjuvant therapy administration by plotting their mean (with
R30
standard deviation) or median (with range) for continuous data when appropriate,
R31
and percentages for categorical data within each group. Differences were tested for
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statistical significance by Oneway ANOVA, the Kruskal-Wallis test, or the Chi-square
R33
test when applicable.
R34 72 | Chapter 6
We assessed the association between lymph node status, with special interest in
R1
the N1micro group, and patient outcome in several ways. Endpoints were defined as
R2
overall survival (OS), disease free survival (DFS) and its individual components (i.e.
R3
locoregional recurrence, contralateral breast cancer, osseal or visceral metastasis).
R4 R5
First, incidence rates of these outcomes were calculated for the total study population.
R6
Then, crude and age adjusted incidence rates for each group were calculated (for
R7
the latter using the indirect standardization method in which N0 group served as the
R8
standard).
R9
R10 Cox proportional hazard analyses were used to assess the risk of adverse patient
R11
outcome for N1micro, N1a, and N≥1b compared to the N0 group. For OS analyses, follow-
R12
up ended at the date of death (event) or either at the date of lost to follow-up or the
R13
end of follow-up (by censoring), whichever occurred first. For DFS analyses, follow
R14
up ended as event at the date of death, locoregional recurrence, contralateral breast
R15
cancer, or metastasis, whichever occurred first (women remaining free of disease
R16
until lost to follow-up or until the end of follow-up were censored at that date). For
R17
analyses regarding risk of metastasis per se, osseal or visceral metastasis, follow-up ended as event at the first occurrence of the specific outcome (women remaining
6
R18
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free of the specific outcome until death, lost to follow-up or end of study were
R20
censored at that date). No Cox proportional hazard analyses were performed for
R21
the risk of locoregional recurrence and contralateral breast cancer as the number of
R22
these events was deemed too small.
R23
R24 Several models were made for each outcome of interest: a model without
R25
adjustment for co-variables (Crude Model); a model with adjustment for age
R26
(continuous), tumor size (continuous) and BR-grade (adjusted model 1); a model
R27
with additional adjustment for adjuvant treatment (adjusted model 2). We explored
R28
whether continuous variables (age and tumor size) were non-linearly related with
R29
the different outcomes by adding quadratic terms to the adjusted model 2. This
R30
did not improve the fit of the models, so transformation of these variables was not
R31
deemed necessary. Categorical variables were entered into the models by making
R32
use of dummy variables.
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R34 Prognostic value of micrometastases: a cohort study | 73
R1
Selection of co-variables to include in the multivariate models was on the basis of a
R2
statistical significant univariate association with lymph node status.
R3
Survival and hazard plots visualizing the relation between lymph node status and
R4
the different outcomes were derived from the Cox proportional hazard analyses
R5
(Adjusted Model 2, plotted in strata of lymph node status at the mean of the co-
R6
variables).
R7
The proportionality of the hazard assumption was checked by log minus log plots and
R8
was not violated for any of the variables in the different models. We also assessed
R9
the magnitude of correlations between all estimates within the different models and
R10
found there was no threat of multicollinearity.
R11
R12
All analyses were performed with SPSS 14.0 (SPSS, Chicago, IL), and all tests were
R13
two-sided with a cut-off for statistical significance of 5%.
R14
R15
Results
R16
R17
At the end of follow-up (August 1, 2007), 636 women of the cohort of 703 women
R18
were still alive (90.5%), 53 had died (7.5%) and 14 were lost to follow-up (2.0%). A
R19
total of 27,760 months of follow-up were accrued, with a median time of follow-up of
R20
40 months. The median age of the patients was 59.4 (range 24.2-92.0) years. There
R21
were 423 patients in the N0 group (60.2%), among them there were 28 patients with
R22
Nitc. There were 81 in the N1micro group (11.5%), 130 in the N1a group (18.5%), and
R23
69 in the N≥1b group (9.8%). This latter group contained 4 (5.8%) patients classified
R24
as N1b, 14 (20.3%) as N1c, 27 (39.1%) as N2a and 24 (34.8%) patients as N3a/b. Various
R25
baseline characteristics were not evenly distributed between the groups (table 1).
R26
Higher nodal status was associated with younger age, larger primary tumor size and
R27
higher BR-grade. The proportions of ER positive, PR positive and Her2/neu positive
R28
tumors were not different for all N-categories.
R29
R30
R31
R32
R33
R34 74 | Chapter 6
72.8% 27.2% 85.8% 63.8% 10.9%
46.3% 33.3% 20.3% 4 (0-92)
13.2% 58.9% 22.7% 5.2%
1.9% 18.0% 80.1% 1.6 (0.8)
N0 (n = 423) 16,889 61.6 (24.2-92.0)
74.1% 25.9% 87.7% 69.1% 8.8%
34.6% 46.9% 18.5% 4 (0-66)
9.9% 45.7% 35.8% 8.6%
0.0% 24.7% 75.3% 1.9 (0.8)
72.3% 27.7% 86.9% 73.1% 5.4%
36.9% 49.2% 13.8% 5 (0-50)
3.8% 50.0% 30.8% 15.4%
1.5% 26.9% 71.5% 2.1 (1.0)
Lymph Node Status N1micro N1a (n = 81) (n = 130) 3,448 5,116 56.5 56.2 (36.3-91.3) (32.4-89.5)
63.8% 36.2% 85.5% 59.4% 17.5%
31.9% 47.8% 20.3% 5 (0-72)
5.8% 37.7% 34.8% 21.7%
5.8% 29.0% 65.2% 2.2 (0.9)
N≥1b (n = 69) 2,308 54.6 (30.5-83.4)
Records with missing values that were imputed (see method section): tumor size: 4; modified Bloom-Richardson grade: 5; Mitotic Activity index: 14; progesterone receptor status: 1 For 120 records Her2/neu status was unknown, these values were not imputed Percentages may not total 100% due to rounding a Median (range) b Mean (standard deviation) Statistical tests: c Kruskall-Wallis; d Oneway ANOVA; e Chi-square
Age (%) < 35 years 35-49 years ≥ 50 years Tumor size (cm)b Tumor size (%) < 1cm 1-2 cm 2-3 cm ≥ 3 cm Bloom-Richardson grade (%) Well differentiated Moderately differentiated Poorly differentiated Mitotic Activity Indexa Mitotic Activity Index (%) < 10 ≥ 10 Estrogen Receptor positive (%) Progesterone Receptor positive (%) Her2/neu positive (%)
Accrued months of follow-up Age (years)a
Characteristic
Table 1. Baseline characteristics according to lymph node status in 703 cT1-2 breast cancer patients
0.46e 0.96e 0.14e 0.08e
0.008e 0.68c
