Sentinel lymph node biopsy for breast cancer •
Updated 2013 May 21 09:57:00 AM: SLN biopsy may have low false negative rate (7.7%) for detection of axillary node metastases in multifocal and multicentric breast cancer (Surgery 2012 Sep) view updateShow more updates
Related Summaries: • •
Breast cancer (list of topics) Breast cancer in women
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Breast cancer in men
Overview: •
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sentinel lymph node (SLN) biopsy is preferred method of axillary lymph node assessment for staging of early breast cancer with no clinical evidence of lymph node involvement Memorial Sloan-Kettering Cancer Center nomogram can predict likelihood of SLN metastasis and likelihood of additional non-SLN metastasis (level 1 [likely reliable] evidence) procedural approach o
combined use of blue dye and isotope-labeled sulfur colloid (intraoperative lymphatic mapping) appears to identify > 90% of sentinel nodes
o
periareolar injection of radiotracer and blue dye may be more effective than peritumoral injection for SLN detection (level 2 [mid-level] evidence)
o
addition of lidocaine to radiocolloid may reduce pain in patients having SLN mapping (level 2 [mid-level] evidence)
specimen analysis o
intraoperative frozen section analysis of SLN may be useful to detect but not rule out metastases due to low sensitivity (level 2 [mid-level] evidence)
o
mammaglobin and cytokeratin 19 mRNA assay (GeneSearch BLN Assay) can detect breast cancer metastases in axillary SLNs (level 1 [likely reliable] evidence)
SLN resection alone is as effective as axillary lymph node dissection (ALND) for survival and regional control in women with invasive breast cancer and clinically negative lymph nodes and negative SLN (level 1 [likely reliable] evidence)
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SLN biopsy associated with reduced morbidity compared to ALND (level 2 [midlevel] evidence)
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management of positive SLN o
axillary lymph node dissection (ALND) has been recommended for patients with positive SLN (micrometastasis or macrometastasis)
o
ALND no longer routinely required for patients with T1-2 tumors and 1-2 positive SLNs without extracapsular extension who will have adjuvant therapies (radiation therapy plus systemic therapy), based on similar tumor recurrence rates and similar 5-year overall survival comparing SLN dissection alone vs. SLN dissection plus ALND (level 2 [mid-level] evidence)
o
ALND still indicated if T3 tumor, preoperative palpable lymph nodes, > 2 positive lymph nodes, matted axillary nodes, or having neoadjuvant chemotherapy
Indications and Contraindications Indications: •
sentinel lymph node (SLN) biopsy is preferred technique for staging axilla for patients with early invasive breast cancer and no evidence of lymph node involvement on clinical exam, ultrasound or ultrasound-guided needle biopsy(1) o if lymphadenopathy on clinical exam or ultrasound, then fine needle aspiration under ultrasound guidance recommended
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SLNB should performed by qualified surgical team(1)
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offer SLNB to all patients having mastectomy for ductal carcinoma in situ (DCIS)(1)
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SLNB not routinely indicated for women having breast conserving surgery for DCIS, unless considered high-risk of invasive disease(1)
Contraindications: • •
no absolute contraindications in patients with invasive breast cancer, but risk of needing further axillary treatment is higher in some patients than others(1) contraindications to SLN biopsy o
absolute contraindications
clinically positive axilla
allergy to blue dye and radio-colloid
o
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relative contraindications
prior surgery of breast and axilla
prior biopsy
advanced disease and neoadjuvant chemotherapy
multicentric disease (separate quadrants)
ductal carcinoma in-situ
pregnancy
Reference - World J Surg Oncol 2007 Jan 29;5:10 full-text
multifocality (multiple foci of same tumor) and multicentricity (multiple synchronous tumors originating in different parts of breast) reported to NOT be contraindication to SLN biopsy o
based on 31 cases
o
periareolar injection (subareolar injection) techniques reported to detect most sentinel lymph nodes
o
Reference - World J Surg Oncol 2006 Nov 20;4:79 full-text
Predicting Lymph Node Metastasis Predicting sentinel lymph node (SLN) metastases: •
Memorial Sloan-Kettering Cancer Center nomogram can predict likelihood of SLN metastasis (level 1 [likely reliable] evidence) o based on derivation and validation cohort study o
3,786 patients having sequential SLN biopsy procedures for invasive breast carcinoma (derivation cohort) were assessed for clinicopathologic features and presence or absence of metastases
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1,545 patients with sequential SLN biopsies included in validation cohort
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33% had SLN metastasis in derivation cohort, 37.5% in validation cohort
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metastasis associated with (p < 0.05)
tumor type, size, and location
lymphovascular invasion
age
multifocality
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o
area under receiver operating characteristic curve for nomogram was 0.754 in validation group
o
Reference - J Clin Oncol 2007 Aug 20;25(24):3670 full-text
tumor size may predict findings on SLN biopsy, but no tumor size can eliminate need for testing (level 2 [mid-level] evidence) o
based on retrospective cohort study
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257 patients had SLN biopsy for invasive breast cancer
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73 (28%) had positive SLN biopsy
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SLN biopsy was positive in
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estrogen and progesterone receptor status
13.5% with T1a tumors
20.4% with T1b tumors
35.9% with T1c tumors
50% with T2 tumors
Reference - Arch Surg 2002 May;137(5):606 full-text
large-gauge needle core breast biopsy associated with increased incidence of SLN metastases compared to excisional breast biopsy (level 2 [mid-level] evidence) o
based on observational study
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663 patients with 676 biopsy-proven invasive breast cancers had SLN dissection
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126 cancers biopsied by fine needle aspiration, 227 biopsied by large-gauge needle core biopsy, 323 biopsied by excisional biopsy
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SLN metastases (compared with excisional biopsy)
increased with core biopsy (odds ratio [OR] 1.48, 95% CI 1.0182.164)
nonsignificant trend toward increase with fine needle aspiration (OR 1.531, 95% CI 0.973-2.406)
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clinical significance unclear
o
Reference - Arch Surg 2004 Jun;139(6):634 full-text
Nomograms for predicting non-sentinel lymph node (SLN) metastasis after positive SLN: •
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nomograms to predict probability of non-SLN metastasis in patients with positive SLN o Stanford Online Calculator (BMC Cancer 2008 Mar 4;8:66 full-text) o
Cambridge University nomogram (Br J Surg 2008 Mar;95(3):302 full-text)
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Tenon nomogram (Breast Cancer Res Treat 2005 May;91(2):113)
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Memorial Sloan Kettering nomogram
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comparison of these nomograms can be found in J Am Coll Surg 2009 Feb;208(2):229
Memorial Sloan-Kettering Cancer Center nomogram and Tenon score associated with most accurate prediction of non-SLN status in patients with breast cancer and SLN metastasis (level 1 [likely reliable] evidence) o
based on comparison of 9 models to predict non-SLN status in cohort of 561 patients with breast cancer and SLN metastasis who had axillary lymph node dissection
o
Reference - J Clin Oncol 2009 Jun 10;27(17):2800 full-text
Sentinel lymph node (SLN) biopsy to predict axillary lymph node metastases: •
SLN biopsy has low false negative rate (7%) and can help rule out axillary metastases in patients with clinically node-negative breast cancer after neoadjuvant chemotherapy (level 1 [likely reliable] evidence) o based on systematic review of diagnostic cohort studies o
systematic review of 10 studies assessing diagnostic performance of SLN biopsy in 449 patients with breast cancer who were clinically node-negative after neoadjuvant chemotherapy
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reference standard was histological analysis of completion axillary lymph node dissection (ALND)
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studies included were published between 2000 and 2008
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SLN identified in 94% patients (range 86%-100%)
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pooled diagnostic performance of SLN biopsy to detect axillary metastases
sensitivity 93% (95% CI 88%-97%)
false negative rate 7% (95% CI 3%-12%, range 0%-17% with 1 outlier of 33% in oldest study)
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Reference - J Surg Oncol 2011 Jul 1;104(1):97
SLN biopsy may have low false negative rate (7.7%) for detection of axillary node metastases in multifocal and multicentric breast cancer (level 2 [midlevel] evidence) o
based on systematic review of diagnostic studies without assessment of trial quality
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systematic review of 16 studies including 932 patients with multifocal and multicentric breast cancer who had SLN biopsy followed by completion axillary lymph node dissection for diagnosis of metastases
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axillary metastases detected in 48% across all studies by axillary lymph node dissection after SLN biopsy (reference standard)
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results limited by heterogeneity of SLN mapping techniques used and variability of inclusion and exclusion criteria in included articles
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diagnostic performance of SLN biopsy for detection of axillary metastases in analysis of all studies
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negative predictive value 94% (95% CI 90%-98%, range 73%-100% with 1 outlier of 57% in oldest study)
pooled sensitivity 92% (95% CI 90-95%)
false-negative rate 7.7%
Reference - Surgery 2012 Sep;152(3):389
conflicting evidence on false negative rates for SLN biopsy may reflect differences in patient samples (resulting in differences in prevalence of axillary node involvement), surgical technique, reference standards, or other variables o
SLN biopsies associated with low false negative rate based on final pathologic exam
based on 2 cohort studies
163 patients with operable breast cancer were tested
52% had axillary metastases
95% negative predictive value for sentinel axillary lymph node on final pathology, but high false negative rate (24%) for frozen sections
o
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Reference - Lancet 1997 Jun 28;349(9069):1864 in J Watch 1997 Aug 1;17(15):119, commentary can be found in Lancet 1997 Sep 13;350(9080):808
206 women with breast cancer and negative SLN were evaluated, median follow-up 26 months
axillary recurrence (as surrogate marker for metastases) in 3 patients (1.4% false negative rate)
Reference - Am J Surg 2002 Oct;184(4):310, commentary can be found in Am Fam Physician 2003 Feb 1;67(3):602
DynaMed commentary -- axillary recurrence at 26 months may not accurately reflect axillary metastases at time of biopsy, because patients may have received treatment following biopsy or had axillary involvement not yet clinically evident at follow-up
SLN biopsy may be useful to detect but not rule out axillary node metastasis, due to 11% false negative rate
based on multicenter validation study
443 patients with breast cancer had attempted sentinel node biopsy then complete axillary lymphadenectomy
sentinel nodes identified in 413 patients, SLN biopsy completed in 405 patients (91%)
axillary nodes positive in 114 (28%) of patients with completed SLN biopsy
sentinel node biopsy had 89% sensitivity, 100% specificity, 100% positive predictive value and 96% negative predictive value for status of axillary nodes
Reference - N Engl J Med 1998 Oct 1;339(14):941 full-text, detailed commentary expressing concern of 11% false negative rate can be found in N Engl J Med 1998 Oct 1;339(14):991, commentary can be found in N Engl J Med 1999 Jan 28;340(4):317
limiting SLN biopsy to 3 sentinel nodes associated with 10% false negative rate (level 2 [mid-level] evidence) o
based on post-hoc analysis of prospective cohort study
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4,131 patients had SLN biopsy then complete axillary node dissection
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1,358 patients with final pathology showing positive lymph nodes were assessed for order in which SLNs were identified and pathologic findings of each
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7.7% false negative rate overall (defined as percentage of node-positive patients in whom SLN biopsy was negative)
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89.7% of positive SLNs found in first 3 sentinel nodes removed (false negative rate 10.3%, p = 0.005 compared to removal of > 3 SLNs)
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Reference - Arch Surg 2007 May;142(5):456 full-text
Other predictors of axillary metastases: •
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guided four node axillary sampling may improve detection of axillary node metastases compared to sentinel node biopsy alone o based on study of 141 patients with node-negative early breast cancer who had guided axillary sampling (sentinel lymph node [SLN] biopsy in combination with axillary sampling) o
four node axillary sampling improve the detection rate of axillary node metastases by 13.6%
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Reference - Int Semin Surg Oncol 2005 Nov 28;2(1):27 full-text
axillary metastases may occur with any histologic subtype o
based on cohort study
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> 3,324 patients had SLN biopsy and axillary dissection for T1-2, N0 breast cancer
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axillary metastases in 35% of patients with infiltrating ductal carcinoma and 40% of patients with infiltrating lobular carcinoma
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axillary metastases by tumor subtype occurred in
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21% of patients with medullary carcinoma
17% of patients with pure tubular carcinoma
8% of patients with ductal carcinoma in situ with microinvasion
7% of patients with papillary cancer
6% of patients with colloid (mucinous) carcinoma
Reference - Am J Surg 2002 Dec;184(6):492
Identifying Sentinel Lymph Nodes
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technetium Tc 99m tilmanocept (Lymphoseek) diagnostic imaging agent FDA approved to help locate tumor-draining lymph nodes in patients with breast cancer or melanoma having surgery (FDA Press Release 2013 Mar 13)
Dual technique: • •
dual technique using isotope and blue dye is recommended approach(1) combined use of blue dye and isotope-labeled sulfur colloid (intraoperative lymphatic mapping) appears to identify > 90% of sentinel nodes o
based on 3 cohort studies
o
500 patients with T1-3N0 breast cancer at 1 institution had sentinel lymph node (SLN) biopsies with isosulfan blue dye and isotope-labeled sulfur colloid
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sentinel nodes identified in 458 patients (92%)
Reference - Ann Surg 1999 Apr;229(4):528 full-text, commentary can be found in Ann Surg 2000 Jan;231(1):148
466 patients with breast cancer had intraoperative lymphatic mapping with combination of vital blue dye and filtered technetium-labelled sulphur colloid
SLN correctly identified in 440 (94.4%) patients
105 patients (23.8%) were positive for malignancy in SLNs, 1 false negative with skip metastasis to higher lymph node
844 SLNs removed
40% positive by technetium-labeled sulfur colloid only
32.2% positive by vital blue dye only
27.6% identified by both methods
incidence of positive sentinel nodes increased with primary tumor size
4.6% with ductal carcinoma in situ
16% for tumors 0.1-1 cm
32.8% for tumors 1-2 cm
40.8% for tumors 2.1-5 cm
75% for tumors > 5 cm
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Reference - Ann Surg 1998 May;227(5):645 full-text, commentary can be found in Ann Surg 1998 Nov;228(5):720
62 patients with newly diagnosed invasive breast cancer had intraoperative lymphatic mapping using vital blue dye and filtered technetium-labeled sulfur colloid
SLN successfully identified in 92% using 2 lymphatic mapping procedures
18 patients (32%) had metastatic disease, all with positive SLN, that is, no "skip" metastases
sentinel node was only positive node in 12 cases
Reference - JAMA 1996 Dec 11;276(22):1818, commentary can be found in JAMA 1997 Mar 12;277(10):791
Periareolar injection: •
periareolar injection of radiotracer and blue dye may be more effective than peritumoral injection for sentinel lymph node (SLN) detection (level 2 [midlevel] evidence) o based on randomized trial with blinding of outcome assessors not stated o
459 patients with biopsy proven T0-T1 invasive breast cancer were randomized to periareolar vs. peritumoral injection sites for SLN detection
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sentinel node detection included radiotracer for preoperative lymphoscintigraphy and blue dye for intraoperative exam and gamma probe
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10 patients excluded for technical difficulties with gamma probe
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detection rates of SLNs comparing periareolar vs. peritumoral injection
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by lymphoscintigraphy 85.2% vs. 73.2% (p = 0.03, NNT 9)
with blue dye 95.6% vs. 93.8% (not significant)
by gamma probe 98.2% vs. 96% (not significant)
mean number of SLNs by lymphoscintigraphy 1.5 vs. 1.2 (p = 0.001)
mean number of SLNs by gamma probe 1.9 vs. 1.7 (p = 0.02)
concordance between blue dye and radiotracer 95.6% vs. 91.5% (p = 0.08)
Reference - FRANSENODE trial (J Clin Oncol 2007 Aug 20;25(24):3664 full-text)
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periareolar injection of radiotracer for SLN biopsy associated with higher SLN detection rate than peritumoral injection (level 2 [mid-level] evidence) o
based on non-randomized trial
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93 patients had SLN biopsy with peritumoral vs. periareolar injection of blue dye
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SLN detection was 100% with periareolar vs. 90% with peritumoral injection (p < 0.05, NNT 10)
o
Reference - Surgery 2002 Mar;131(3):277
Contribution of lymphoscintigraphy: •
lymphoscintigraphy may reduce post-procedural pain, numbness or paresthesia associated with sentinel lymph node (SLN) biopsy (level 2 [midlevel] evidence) o based on systematic review of cohort studies o
systematic review of 13 studies reporting pain, numbness or paresthesia after SLN biopsy with vs. without lymphoscintigraphy
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symptoms > 9 months after procedure comparing studies using lymphoscintigraphy vs. studies not using lymphoscintigraphy
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pain in 13.8% of 1,347 patients in 7 studies vs. 28.7% of 143 patients in 1 study (p < 0.0001)
numbness or paresthesia in 12.5% of 601 patients in 6 studies vs. 23.1% of 229 patients in 3 studies (p = 0.0002)
Reference - World J Surg Oncol 2005 Sep 29;3:64 full-text
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review of lymphoscintigraphy and triangulated body marking for morbidity reduction during sentinel node biopsy in breast cancer can be found in Int Semin Surg Oncol 2005 Nov 8;2:25 full-text
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editorial review of preoperative lymphoscintigraphy and triangulated patient body marking can be found in World J Surg Oncol 2005 Aug 24;3:56 full-text
Analgesia: •
addition of lidocaine to radiocolloid may reduce pain in patients having sentinel lymph node (SLN) mapping (level 2 [mid-level] evidence) o based on randomized trial without intention-to-treat analysis o
140 patients with early breast cancer randomized to 1 of 4 regimens
topical 4% lidocaine cream and technetium-99m-sulfur colloid injection alone
placebo cream and technetium-99m-sulfur colloid injection with sodium bicarbonate
placebo cream and technetium-99m-sulfur colloid injection with 1% lidocaine
placebo cream and technetium-99m-sulfur colloid injection with sodium bicarbonate plus1% lidocaine
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121 patients (86%) included in analysis
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pain scores were significantly lower in both groups receiving lidocaine injection (p < 0.0001)
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no significant difference between groups for SLN identification (90%-97% range)
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Reference - Lancet Oncol 2009 Sep;10(9):849, editorial can be found in Lancet Oncol 2009 Sep;10(9):838
Adverse effects: •
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injection of methylene blue dye for sentinel lymph node biopsy associated with skin and fat necrosis followed by dry gangrene of skin in case report (Int Semin Surg Oncol 2005 Nov 28;2:26 full-text) preoperative prophylaxis may reduce risk for severe adverse reactions to isosulfan blue dye (level 3 [lacking direct] evidence) o
based on before-and-after study
o
667 women having sentinel lymph node biopsy with isosulfan (Lymphazurin) blue dye were given preoperative prophylaxis with steroid (hydrocortisone 100 mg, methylprednisolone 20 mg, or dexamethasone 4 mg), diphenhydramine 50 mg, and famotidine 20 mg IV before or at induction of anesthesia
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3 women (0.5%) had reaction to dye (blue urticaria and facial edema), all reactions were grade 1
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in women who received isosulfan blue dye without prophylaxis
in 12 women in this study who did not get complete prophylaxis as protocol violation, 1 (8.3%) had adverse reaction
in 639 women having same procedure without prophylaxis in a prior study, 7 (1.1%) had severe anaphylactoid reaction requiring vigorous resuscitation
o
Reference - Cancer 2005 Aug 15;104(4):692 full-text
Specimen Evaluation Intraoperative frozen section analysis: •
intraoperative frozen section analysis of sentinel lymph node (SLN) may be useful to detect but not rule out metastases due to low sensitivity (level 2 [midlevel] evidence) o based on retrospective cohort study of 326 women and meta-analysis of 47 studies of 13,062 women with breast cancer and intraoperative frozen section analysis of SLN o
30% of cohort had SLN metastasis
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intraoperative frozen section analysis associated with
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61% sensitivity (29% for detecting micrometastasis vs. 80% for macrometastasis) and 100% specificity in cohort study
73% sensitivity (40% for detecting micrometastasis vs. 94% for macrometastasis) and 100% specificity in meta-analysis
Reference - Cancer 2011 Jan 15;117(2):250
intraoperative frozen section may be more accurate than imprint cytology for assessment of SLN o
based on cohort study
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138 women with stage I breast cancer had sentinel node biopsy with evaluation by intraoperative frozen section and postoperative imprint cytology
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17 patients (12%) had sentinel node involvement
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frozen section had 88% sensitivity and 100% specificity
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imprint cytology had 47% sensitivity and 98% specificity
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Reference - World J Surg Oncol 2006 May 17;4:26 full-text
Immunohistochemistry: •
mammaglobin and cytokeratin 19 mRNA assay (GeneSearch BLN Assay) o molecular-based laboratory test (GeneSearch BLN Assay) FDA approved for detection of breast cancer metastases in lymph nodes
o
compared with extensive microscopic exam in 416 patients, GeneSearch BLN Assay had 88% sensitivity and 94% specificity for breast cancer metastasis in lymph nodes
compared with immediate microscopic exam during surgery, GeneSearch BLN Assay had fewer false negative but slightly more false positive tests
Reference - FDA Press Release 2007 Jul 16
mammaglobin and cytokeratin 19 mRNA assay (GeneSearch BLN Assay) can detect breast cancer metastases in axillary sentinel lymph nodes (SLN) (level 1 [likely reliable] evidence)
based on diagnostic cohort study
293 SLNs from 293 patients were evaluated using real-time reversetranscription-polymerase chain reaction (PCR) assay for mammaglobin and cytokeratin 19 mRNAs and histopathologic exam as reference standard
72 metastatic SLNs were identified by histopathology
for detection of metastases by reverse-transcription-PCR assay
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98.1% sensitivity to detect metastases > 2 mm
94.7% sensitivity to detect metastases > 1 mm
77.8% sensitivity to detect metastases > 0.2 mm
95% specificity
83.6% positive predictive value
92.9% negative predictive value
Reference - Ann Surg 2008 Jan;247(1):136
cytokeratin 19 mRNA one step nucleic acid amplification (OSNA-CK19) may be useful for intra-operative analysis of lymph node metastases o
based on 2 diagnostic cohort studies
o
sentinel lymph nodes from 204 patients with breast cancer were examined intraoperatively by OSNA-CK19 and histopathology (reference standard)
concordance rate between OSNA-CK19 and histopathology was 96%
for identification of metastases, OSNA-CK19 had sensitivity 91.7% and specificity 96.9%
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Reference - Br J Surg 2011 Apr;98(4):527
346 frozen axillary lymph node samples from 32 women with breast cancer tested
half of nodes tested via OSNA-CK19
half of nodes tested via histologic staining
OSNA-CK19 associated with 95.3% sensitivity and 94.7% specificity compared to histology
Reference - Int J Cancer 2008 Jun 1;122(11):2562 full-text
nongenetic immunohistochemistry analysis less used currently for clinical decisionmaking o
o
immunohistochemistry of histologically negative axillary lymph nodes may alter clinical management (level 2 [mid-level] evidence)
based on study of 52 patients
immunohistochemistry (by pancytokeratin antibody) of histologically negative axillary lymph nodes resulted in upstaging of SLN in 8 patients (14%)
resulting information would have altered clinical management in 6 patients
Reference - Lancet 1999 Aug 14;354(9178):570, commentary can be found in Lancet 1999 Dec 4;354(9194):1998
addition of immunohistochemical staining and multiple-level sectioning may increase sensitivity of SLN evaluation (level 2 [mid-level] evidence)
based on retrospective cohort study
84 patients with breast cancer with sentinel node biopsy and axillary dissection had sentinel node specimens evaluated by 2 levels of hematoxylin-eosin staining and immunohistochemical stains for keratin
hematoxylin-eosin staining detected metastases in 20 patients (23.8%)
immunohistochemical staining detected nodes positive for micrometastases in 5 of 64 patients with negative nodes by hematoxylin-eosin staining (7.8%)
Reference - Arch Pathol Lab Med 2003 Jun;127(6):701 full-text
o
cytokeratin staining of 0.25 mm serial sections of SLN appears to detect metastases better than hematoxylin-eosin staining of 2 mm sections (level 2 [mid-level] evidence)
based on cohort study
52 patients with invasive breast carcinomas studied
SLNs cut at 2 mm intervals and stained with hematoxylin and eosin compared to SLNs cut at 0.25 mm intervals and stained with cytokeratin
metastases identified in 12% with hematoxylin and eosin stain vs. 58% with cytokeratin stain
long-term follow-up necessary to determine clinical significance
Reference - Cancer 1999 Sep 15;86(6):990 full-text, editorial can be found in Cancer 1999 Sep 15;86(6):905
Clinical Outcomes Survival and tumor control: •
sentinel lymph node (SLN) resection alone is as effective as axillary lymph node dissection (ALND) for survival and regional control in women with invasive breast cancer and clinically negative lymph nodes and negative SLN (level 1 [likely reliable] evidence) o based on randomized trial o
5,611 women with invasive breast cancer and clinically negative nodes randomized to SLN resection alone (plus ALND only if SLN positive) vs. SLN resection plus ALND
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women followed for mean 96 months
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3,986 women (71%) with negative SLN included in primary analysis
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7.8% overall mortality
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comparing SLN resection alone vs. SLN resection plus ALND
8-year overall survival 90.3% vs. 91.8% (not significant)
8-year disease free survival 81.5% vs. 82.4% (not significant)
local recurrence in 2.4% vs. 2.7% (not significant)
regional node recurrence in 0.7% vs. 0.4% (not significant)
distant metastasis in 3.2% vs. 2.8% (not significant)
o
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cancer in opposite breast in 2.2% vs. 2.8% (not significant)
second non-breast cancer in 5.4% vs. 4.5% (not significant)
grade 3 or higher surgery-related adverse event in 0.4% vs. 0.5% (not significant)
Reference - National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial (Lancet Oncol 2010 Oct;11(10):927), editorial can be found in Lancet Oncol 2010 Oct;11(10):908
sentinel node biopsy appears to be safe alternative to axillary dissection for women with breast tumors ≤ 2 cm (level 2 [mid-level] evidence) o
based on randomized trial with randomization method not stated
o
516 women with primary breast cancer and tumor ≤ 2 cm in diameter were randomized to sentinel node biopsy and total axillary dissection vs. sentinel node biopsy and axillary dissection only if sentinel node contained metastases
o
comparing axillary node dissection vs. SLN biopsy with axillary dissection if positive
sentinel node positive in 32.3% vs. 35.5% (not significant)
breast cancer events (such as metastasis or recurrence) in 15 vs. 10 patients (not significant)
o
patients spared axillary dissection had less pain and better arm mobility
o
no cases of overt axillary metastasis during median 46-month follow-up of 167 patients who did not have axillary dissection
o
Reference - N Engl J Med 2003 Aug 7;349(6):546 full-text, editorial can be found in N Engl J Med 2003 Aug 7;349(6):603, commentary can be found in N Engl J Med 2003 Nov 13;349(20):1968, Am Fam Physician 2004 Mar 15;69(6):1552, Lancet Oncol 2006 Dec;7(12):964
o
axillary dissection only after sentinel confirmation of metastases may not increase unfavorable results and death (level 2 [mid-level] evidence)
based on 10-year follow-up of randomized trial above
no significant difference in unfavorable results in dissection with metastases confirmation vs. dissection in all
breast-cancer related events
other primary tumors
deaths
Reference - Ann Surg 2010 Apr;251(4):595, editorial can be found in Ann Surg 2010 Apr;251(4):601
Upper extremity and related morbidity: •
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sentinel lymph node (SLN) biopsy associated with reduced morbidity compared to axillary lymph node dissection (level 2 [mid-level] evidence) o based on systematic review of trials without blinding o
systematic review of 7 trials comparing SLN biopsy vs. axillary lymph node dissection for detecting metastases with 9,608 patients
o
SLN biopsy associated with reduced
wound infection (odds ratio [OR] 0.58, 95% CI 0.42-0.8) in analysis of 3 trials with 2,781 patients
seroma (OR 0.4, 95% CI 0.31-0.51) in analysis of 3 trials with 2,125 patients
limb swelling (OR 0.3, 95% CI 0.14-0.66) in analysis of 5 trials with 2,154 patients, results limited by heterogeneity (p = 0.0009)
numbness (OR 0.25, 95% CI 0.1-0.59) in analysis of 5 trials with 3,265 patients, results limited by heterogeneity (p < 0.0001)
o
no significant difference between treatments in detecting lymph node metastases
o
Reference - Breast Cancer Res Treat 2010 Apr;120(2):441
SLN biopsy may reduce surgical morbidity and persistent complications compared to axillary dissection (level 2 [mid-level] evidence) o
based on randomized trial with allocation concealment not stated
o
1,031 patients < 80 years old having wide excision or mastectomy for clinically node-negative invasive breast cancer were randomized to SLN biopsy vs. standard axillary surgery (level I-III axillary lymph node dissection or 4-node axillary sampling)
o
SLN biopsy used preoperative lymphoscintigraphy with technetium-99mTcalbumin colloid (Nanocoll) and blue dye injected peritumorally
all blue-stained nodes and positive nodes on handheld gamma probe were removed as SLNs
if SLNs not identified, then standard axillary treatment done
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o
SLNs were examined by hematoxylin-eosin stains postoperatively
o
patients with positive SLN findings offered delayed axillary lymph node dissection or axillary radiation therapy
o
trial terminated early due to recognition of less arm and shoulder morbidity with SLN biopsy
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816 patients (79% originally randomized, 82% those who received initial treatment) were analyzed at 1 year, intention-to-treat analysis did not account for dropouts
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comparing SLN biopsy vs. axillary dissection at 1 year
lymphedema in 5% vs. 13% (NNT 13)
sensory loss in 11% vs. 31% (NNT 5)
axillary local recurrence in 0.2% vs. 1% (not significant)
mortality 1.7% vs. 1.7%, including 0.5% vs. 0.5% due to metastatic breast carcinoma (not significant)
o
SLN biopsy associated with shorter durations of operative time, drain use, hospital stay, and return to normal activities
o
Reference - ALMANAC trial (J Natl Cancer Inst 2006 May 3;98(9):599 full-text), editorial can be found in J Natl Cancer Inst 2006 May 3;98(9):568, commentary can be found in Can J Surg 2008 Dec;51(6):483
SLN resection alone associated with reduced risk of upper extremity complications at 3 years compared to axillary lymph node dissection (level 2 [mid-level] evidence) o
based on 3-year follow-up of NSABP B-32 trial with high loss to follow-up
o
73% of women with SLN node-negative breast cancer participated in 3-year follow-up
o
comparing SLN alone vs. SLN plus ALND
shoulder abduction deficits ≥ 10% at 6 months in 5.7% vs. 9% (p < 0.001, NNT 31)
arm volume difference ≥ 10% at 3 years in 7.5% vs. 14.3% (p < 0.001, NNT 15)
residual arm tingling at 3 years in 7.5% vs. 13.5% (p < 0.001, NNT 17)
o •
•
residual arm numbness at 3 years in 8.1% vs. 31.1% (p < 0.001, NNT 5)
Reference - J Surg Oncol 2010 Aug 1;102(2):111, editorial can be found in J Surg Oncol 2010 Aug 1;102(2):109
SLN resection alone associated with reduced arm symptoms and less impairment on activities and quality of life compared to axillary lymph node dissection (level 2 [mid-level] evidence) o
based on subgroup analysis of 749 women with negative SLN from NSABP B-32 trial who completed questionnaires
o
SLN plus ALND associated with significantly more
bothersome arm symptoms
ipsilateral arm and breast symptoms
restricted work and social activity
impaired quality of life
o
< 15% of all women reported any moderate or severe symptom or activity limitation at 12-36 months
o
Reference - J Clin Oncol 2010 Sep 1;28(25):3929
restricted shoulder symptoms common 2 weeks postoperatively but less frequent in women with SLN biopsy alone than SLN biopsy plus axillary dissection (level 2 [mid-level] evidence) o
based on prospective cohort study
o
49 women undergoing sentinel node biopsy alone and 36 women undergoing traditional SNB with axillary dissection were evaluated
o
comparing sentinel node biopsy alone vs. traditional dissection
restricted shoulder abduction and flexion at 2 weeks in 45% vs. 86% (p = 0.002, NNT 3 favoring biopsy alone)
axillary web syndrome in 20% vs. 72% (p < 0.0001, NNT 2 favoring biopsy alone)
subjective shoulder restriction at 2 weeks in 80% vs. 100% (NNT 5 favoring biopsy alone)
o
almost all patients had full range of motion at 3 months
o
Reference - Am J Surg 2003 Feb;185(2):127, commentary can be found in Am Fam Physician 2003 Sep 1;68(5):967
Management of Positive Sentinel Lymph Nodes (SLN) Classification of lymph node disease: •
lymph node disease (small deposits of metastatic tumor in lymph nodes) classified as(1) o macrometastatic disease if > 2 mm
o
o
•
patient classified as lymph node-positive
mean proportion of patients with non-sentinel lymph node (SLN) metastases 53.2% for patients with SLN macrometastases in 8 observational studies
micrometastatic if < 2 mm (0.2-2 mm)
patient classified as lymph node-positive
mean proportion of patients with non-SLN metastases 17.7% for patients with SLN micrometastases in 8 observational studies
pooled estimates for rate of non-SLN metastases in patients with SLN micrometastases in 2 systematic reviews
20.2% when SLN metastases detected by hematoxylin and eosin (H&E) staining
9.4% when SLN metastases detected by immunohistochemistry techniques
isolated tumor cells (< 0.2 mm)
single cells or tiny clusters of cells, usually detected by immunohistochemistry
patient classified as lymph node-negative
mean proportion of patients with non-SLN metastases 10% for patients with SLN isolated tumor cells in 8 observational studies
staging of nodal disease can be subclassified to note isolated tumor cells or micrometastases o
patients with no regional lymph node metastases (N0) may be subclassified as
pN0 no regional lymph node metastases identified histologically
pN0(i-) no regional lymph node metastases identified histologically and negative immunohistochemistry
o
•
•
pN0(i+) malignant cells in regional lymph node(s) no greater than 0.2 mm (isolated tumor cells)
metastases to movable ipsilateral level I or II axillary lymph nodes (N1) may be further classified as
pN1 micrometastases, or metastases in 1-3 axillary lymph nodes, and/or metastases in internal mammary nodes detected by sentinel lymph node biopsy but not by imaging or clinica exam
pN1mi micrometastases (> 0.2 mm and/or > 200 cells, but < 2 mm)
pN1a metastases in 1-3 axillary lymph nodes with at least 1 metastasis > 2 mm
pN1b metastases in internal mammary nodes with micrometastases or macrometastases in internal mammary nodes detected by sentinel lymph node biopsy but not by imaging or clinical exam
pN1c is combination of pN1a and pN1b
o
Reference - information, including clinical staging form and information on pathologic classification, can be found at AJCC PDF
o
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer SBM, LLC.
clinical relevance of SLN isolated tumor cells unclear o
based on literature review
o
SLN isolated tumor cells associated with marginally poorer prognosis
o
identification of isolated tumor cells varies with analytic technique
o
no strong evidence to guide management decisions based on identification of isolated tumor cells
o
Reference - Breast Cancer Res Treat 2011 Jun;127(2):325
prognostic significance of SLN micrometastases uncertain o
based on literature review
o
11 studies did not find evidence of effect of SLN micrometastases on overall survival, distant metastasis, axillary recurrence, disease-free survival, or metastasis-free survival
o
5 studies found association with overall survival, distant metastases, or disease-free survival
o
Reference - Surg Oncol 2011 Dec;20(4):e195
Recommendations: •
•
National Institute for Health and Clinical Excellence (NICE) recommendations(1) o offer further axillary treatment to patients with early invasive breast cancer who have
macrometastases or micrometastases shown in a sentinel lymph node (SLN)
preoperative ultrasound-guided needle biopsy with histologically proven metastatic cancer
o
axillary lymph node dissection (ALND) is preferred over axillary radiation therapy because it provides additional staging information, or consider clinical trials comparing axillary radiation therapy with completion ALND in early breast cancer patients with axillary metastasis found by SLN biopsy
o
further axillary treatment not recommended for patients with only isolated tumor cells in sentinel lymph nodes (such patients should be considered lymph node-negative)
American Society of Breast Surgeons (ASBS) position statement on management of axilla in patients with invasive breast cancer o
o
axillary lymph node dissection (ALND) may no longer be routinely required for patients who meet all criteria below
T1-2 tumors
1-2 positive sentinel lymph nodes without extracapsular extension
patient acceptance and completion of both
whole breast radiation therapy without extended fields of therapy
adjuvant therapy (hormonal, cytotoxic, or both)
recommendation to omit ALND does not directly apply to patients who
have T3 tumors
have > 2 positive nodes
are having mastectomy
o
o
are having partial breast radiation
have matted axillary nodes or palpable nodes preoperatively
are having neoadjuvant chemotherapy
recommendations for specimen evaluation from sentinel lymph node (SLN) biopsy
routine use of immunohistochemistry (IHC) no longer recommended, based on 2 studies suggesting SLN micrometastases detected by IHC staining are clinically insignificant
intraoperative frozen-section of sentinel lymph nodes can be avoided if clinical suspicion of nodal involvement low and patient otherwise meets criteria above for avoiding ALND
Reference - ASBS 2011 Aug 31 PDF
Patients who may not benefit from axillary dissection: •
sentinel lymph node (SLN) dissection alone and SLN dissection plus axillary lymph node dissection (ALND) may have similar tumor recurrence rates and similar 5-year overall survival in selected women with 1-2 SLN metastases who receive adjuvant radiation therapy and systemic therapy (level 2 [mid-level] evidence) o based on randomized trial with inadequate statistical power o
o
891 women ≥ 18 years old with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1-2 SLN metastases were randomized to completion ALND following SLN dissection vs. no ALND
all patients had SLN dissection and lumpectomy prior to randomization
adjuvant systemic therapy given at physician/patient discretion (92.7% received adjuvant systemic therapy including 55.7% given chemotherapy and 44.7% given hormone therapy)
all patients received adjuvant radiation therapy to whole breast
exclusion criteria included
matted nodes or ≥ 3 involved SLNs
gross extranodal disease
treatment with neoadjuvant chemotherapy or hormonal therapy
bilateral breast cancer or multicentric disease
history of ipsilateral axillary surgery
o
power analysis estimated 1,900 patients required to detect hazard ratio of 1.3 for overall survival, recruitment stopped early due to low event rates in both arms
o
modified intention-to-treat population excluded 35 women who withdrew following SLN dissection
o
size of SLN metastasis was micrometastasis in 35%, macrometastasis in 50%, and unknown in 15%
o
comparing ALND vs. no ALND at median follow-up 6.3 years
local recurrence in 3.6% vs. 1.8% (not significant)
regional recurrence in ipsilateral axilla in 0.5% vs. 0.9% (not significant)
adjuvant systemic therapy in 96% vs. 97% (not significant)
o
median times to local recurrence-free survival and regional recurrence-free survival not reached in either group
o
Reference - American College of Surgeons Oncology Group Z0011 randomized trial (Ann Surg 2010 Sep;252(3):426), commentary can be found in Ann Surg 2011 Dec;254(6):1078
o
similar 5-year overall survival in post-hoc analysis of this trial
criterion for noninferiority of SLN dissection alone was 1-sided hazard ratio < 1.3
median follow-up 6.3 years
comparing ALND vs. no ALND
5-year overall survival 91.8% vs. 93.5% (not significant)
5-year disease-free survival 82.2% vs. 83.9% (not significant)
Reference - JAMA 2011 Feb 9;305(6):569, editorial can be found in JAMA 2011 Feb 9;305(6):606
Timing of axillary dissection: •
in women with sentinel lymph node (SLN) metastases, immediate completion axillary lymph node dissection (cALND) may be associated with more paresthesias for first 6 months and impaired range of motion for first 30 days compared to delayed completion axillary lymph node dissection (level 2 [midlevel] evidence)
o
based on observational study
o
1,003 women with SLN metastases and cALND evaluated
425 women had immediate cALND (concurrent with SLN biopsy)
578 women had delayed cALND (median 19 days, range 1-93 days)
o
SLN metastases not further classified as macrometatastases and micrometastases in this study
o
complications at 30 days comparing immediate vs. delayed cALND
o
o
o
paresthesia in 51% vs. 35% (p < 0.0001)
impaired range of motion in 49% vs. 36% (p < 0.0001)
lymphedema in 8% vs. 8% (not significant)
axillary seromas occurred in 18% immediate vs. 12% delayed cALND (p = 0.01)
wound infection in 7% vs. 8% (not significant)
complications at 6 months comparing immediate vs. delayed cALND
paresthesia in 50% vs. 42% (p = 0.03)
impaired range of motion in 4% vs. 4% (not significant)
lymphedema in 10% vs. 13% (not significant)
complications at 1 year comparing immediate vs. delayed cALND
paresthesia in 36% vs. 38% (not significant)
impaired range of motion in 6% vs. 5% (not significant)
lymphedema in 14% vs. 12% (not significant)
Reference - J Clin Oncol 2008 Jul 20;26(21):3530 full-text
Quality Improvement Physician Quality Reporting System Quality Measures: •
99. Breast Cancer Resection Pathology Reporting: pT Category (Primary Tumor) and pN Category (Regional Lymph Nodes) with Histologic Grade o Percentage of breast cancer resection pathology reports that include the pT category (primary tumor), the pN category (regional lymph nodes), and the histologic grade
•
264. Sentinel Lymph Node Biopsy for Invasive Breast Cancer o
•
Percentage of clinically node negative (clinical stage T1N0M0 or T2N0M0) breast cancer patients who undergo a sentinel lymph node (SLN) procedure
see Physician Quality Reporting System Quality Measures for additional information
Guidelines and Resources Guidelines: United States guidelines: •
American Society of Clinical Oncology (ASCO) recommendations on sentinel lymph node biopsy in early-stage breast can cancer can be found in J Clin Oncol 2005 Oct 20;23(30):7703 full-text, commentary can be found in J Clin Oncol 2006 Jan 1;24(1):210
•
American Society of Breast Surgeons (ASBS) o
ASBS position statement on management of axilla in patients with invasive breast cancer can be found at ASBS 2011 Aug 31 PDF
o
ASBS guidelines for performing sentinel lymph node biopsy in breast cancer can be found at ASBS 2010 Nov 5 PDF
United Kingdom guidelines: •
National Institute for Health and Clinical Excellence (NICE) guidelines o guideline on diagnosis and treatment of early and locally advanced breast cancer can be found at NICE 2009 Feb:CG80 PDF or at National Guideline Clearinghouse 2009 Sep 21:14312, commentary can be found in BMJ 2009 Feb 25;338:b438 o
guideline on diagnosis and treatment of advanced breast cancer can be found at NICE 2009 Feb:CG81 PDF or at National Guideline Clearinghouse 2009 Sep 21:14311, summary can be found in BMJ 2009 Feb 25;338:b509
Canadian guidelines: •
Alberta Health Services (AHS) clinical practice guideline on sentinel lymph node biopsy and axillary node dissection in early stage breast cancer can be found at AHS 2012 Aug PDF or at National Guideline Clearinghouse 2013 Mar 11:38592
European guidelines:
•
European Society of Medical Oncology (ESMO) clinical practice guidelines on primary breast cancer (diagnosis, treatment and follow-up) can be found in Ann Oncol 2011 Sep;22 Suppl 6:vi12 full-text
•
expert recommendations for pathological examination and histological report for breast cancer specimens in Marche Region can be found in Pathologica 2011 Oct;103(5):294
Australian and New Zealand guidelines: •
New Zealand Guidelines Group (NZGG) guideline on management of early breast cancer can be found at NZGG 2009 Aug PDF or at National Guideline Clearinghouse 2009 Aug:15462
Review articles: • •
review of quality indicators for sentinel lymph node biopsy in breast cancer can be found in Ann Surg Oncol 2010 Feb;17(2):579 case presentation of breast cancer with isolated tumor cells in sentinel lymph node can be found in N Engl J Med 2005 Nov 17;353(20):2177
•
editorial review of sentinel lymph node biopsy can be found in BMJ 2004 Jun 5;328(7452):1330 full-text, commentary can be found in BMJ 2004 Jul 17;329(7458):170
•
commentary against using sentinel node biopsy can be found in Lancet 2000 Aug 19;356(9230):682, commentary can be found in Lancet 2000 Nov 18;356(9243):1770
Patient Information • handout from National Cancer Institute PDF References General references used: •
1. National Institute for Health and Clinical Excellence (NICE). Early and locally advanced breast cancer: diagnosis and treatment. NICE 2009 Feb:CG80 PDF or at National Guideline Clearinghouse 2009 Sep 21:14312, commentary can be found in BMJ 2009 Feb 25;338:b438
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Special acknowledgements: •
Ranjna Sharma, MD (Instructor in Surgery, Harvard Medical School; Beth Israel Deaconess Medical Center – Breast Cancer Center; Massachusetts, United States) provides peer review.