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ORIGINAL SCIENTIFIC ARTICLES

rognostic Implications of Isolated Tumor Cells andicrometastases in Sentinel Nodes of Patients with

nvasive Breast Cancer: 10-Year Analysis of Patientsnrolled in the Prospective East Carolina University/nne Arundel Medical Center Sentinel Nodeulticenter Study

ennifer Reed, MD, Martin Rosman, MD, Kathryn M Verbanac, PhD, Ann Mannie, PhD,andra Cheng, MD, FACS, Lorraine Tafra, MD, FACS

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a more sensitive and accurate nodal staging proce-dure than axillary lymph node dissection (ALND). Because of increased pathologic evalu-ation in the sentinel node era, more nodal micrometastases (MIC) (� 0.2 mm to 2 mm)and isolated tumor cells (ITC; � 0.2 mm) have been identified. We present the 10-yearanalysis of our prospective SLN study, focusing on regional axillary node status and distantmetastases in patients with nodal ITC and MIC.

STUDY DESIGN: From 1996 to 2005, breast cancer patients were enrolled in an Institutional Review Board-approved, multicenter study. SLNs were examined at multiple levels by hematoxylin and eosin;most (85%) hematoxylin and eosin-negative SLNs were also examined by cytokeratin immu-nohistochemistry. Data from 1,259 patients with invasive breast cancer and in whom an SLNwas found were reviewed for this analysis.

RESULTS: Of the 1,259 patients, 893 (71%) had negative SLNs, 25 (2%) had ITCs, 57 (5%) had MIC, and284 (23%) had positive SLNs. None of the 13 patients with ITCs who underwent an ALND hadadditional positive nodes, compared with 27% (11 of 41) of patients with MIC. At a mean followupof4.9years, thedistant recurrence rates forSLN-negative, ITC,MIC,andSLN-positivegroupswere6%,8%, 14%, and 21%, respectively.The presence of MIC in the SLN was associated with a significantlyshorter disease-free interval than was SLN negativity (p � 0.02 by Cox regression model).

CONCLUSIONS: This prospective breast cancer study found that sentinel node MIC, but not ITCs, were asso-ciated with additional positive nodes and with distant recurrence. These data suggest thatALND may be unnecessary in patients with ITCs. But ALND and more aggressive adjuvanttherapy should be considered in patients with SLN micrometastases. ( J Am Coll Surg 2009;

208:333–340. © 2009 by the American College of Surgeons)

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etastasis to regional lymph nodes is the most impor-ant prognostic factor in the breast cancer patient. Axil-

isclosure Information: Nothing to disclose.upported by grants from the Department of Defense Breast Cancer Researchrogram (DAMD 17–98–1–8079 to LT and DAMD 17–00–1–0239 to KMV).

eceived August 27, 2008; Revised October 16, 2008; Accepted October 27,008.rom The Breast Center for Anne Arundel Medical Center, Annapolis, MDReed, Rosman, Cheng, Tafra), and Department of Surgery, East Carolinaniversity, Greenville, NC (Verbanac, Mannie).orrespondence address: Lorraine Tafra, MD, The Breast Center, 2002 Med-

Ocal Parkway, Suite 120, Annapolis, MD 21401.

3332009 by the American College of Surgeons

ublished by Elsevier Inc.

ary lymph node status has been historically determinedy a complete axillary lymph node dissection (ALND)ollowed by pathologic evaluation of each node with aingle section stained with hematoxylin and eosinH&E). Multiple studies in the past decade have shownhat this method of pathologic evaluation may miss oc-ult metastases. Cote and colleagues1 reported a seminaletrospective study of 736 patients whose lymph nodesere initially negative for metastasis by routine histol-gy. These nodes were reexamined with serial sectioning&E and single section immunohistochemistry (IHC).

ccult metastases identified by IHC (n � 148; 20%)

ISSN 1072-7515/09/$36.00doi:10.1016/j.jamcollsurg.2008.10.036

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334 Reed et al Isolated Tumor Cells in Sentinel Nodes J Am Coll Surg

ere an independent predictor of recurrence in post-enopausal patients, at a median followup of 12 years

p � 0.007).Sentinel lymph node biopsy (SLNB) has become a stan-

ard diagnostic procedure in the clinically node-negativereast cancer patient and, because fewer nodes are evalu-ted than with an ALND, increased pathologic evaluations more feasible and more routine. This more comprehen-ive nodal analysis has resulted in increased detection ofetastatic and micrometastatic disease, by both H&E and

HC.2-5

In 2003, the American Joint Committee on CancerAJCC) revised the breast cancer staging system (6th edi-ion), with particular attention to the distinction of micro-etastases (MIC) and isolated tumor cells (ITC). This re-

ision classifies ITC (� 0.2 mm) as node negative, pN0i�). ITC are defined as single tumor cells or clusters usu-lly detected only by IHC or molecular methods, but thatay be verified on H&E stain. MIC (� 0.2 mm to 2 mm)

re now classified as node positive (pN1mi). These recenthanges to the AJCC staging for lymph nodes containingTC and MIC have standardized how these metastases arelassified, but the prognostic significance, the need forLND, and the need for more aggressive systemic treat-ent in these patients are still in question. To evaluate the

ignificance and prognostic implications of ITC and MIC,e present longterm followup data from a prospective sen-

inel lymph node (SLN) clinical trial6 focusing on distantetastases in patients with lymph nodes containing ITC

nd MIC.

ETHODSatients and clinical protocoln Institutional Review Board-approved, multicenter sen-

inel node study was initiated in 1996, enrolling 1,419atients at 16 sites, including academic centers and com-unity hospitals, as previously described.6 Multiple prog-

ostic variables in patients with breast cancer were main-ained in a prospective database as a part of the study. There

Abbreviations and Acronyms

AJCC � American Joint Committee on CancerALND � axillary lymph node dissectionH&E � hematoxylin and eosinIHC � immunohistochemistryITC � isolated tumor cellsMIC � micrometastasesSLN � sentinel lymph nodeSLNB � sentinel lymph node biopsy

ere 1,259 (89%) patients enrolled from 1996 to 2005, c

ho had invasive breast cancer and had at least one sentinelode identified. Both private-practice and academic sur-eons were recruited as investigators for the study afterarticipating in a course on SLNB techniques. Tc99 andsosulfan blue or other dyes were injected into the peritu-

oral region. The Tc99 was also injected intradermally athe site of the tumor or in the nipple areolar complex inost patients. A gamma probe was then used intraopera-

ively to assist in finding the sentinel node, which wasecorded as hot (10 � background), blue, or hot and blue.fter an initial validation series, some of the more experi-nced surgeons managed their patients with only SLNB,ithout a backup axillary node dissection, when no addi-

ional disease was identified on pathologic evaluation of theLN. Of the 1,259 patients, 58% had a total axillary dis-ection. Stage IV patients were excluded from the trial, butatients with other malignancies or an earlier breast cancerere not.

athologic examination of lymph nodesentinel nodes were serially sectioned, and alternate 2-mmections were formalin-fixed and embedded in paraffin foristologic examination. Alternate sections were frozen andanked for an ongoing molecular analysis study. Sentinelodes were serially sectioned at multiple levels and exam-

ned with H&E staining. The majority (85%) of the pa-ients were enrolled at centers that performed IHC with aytokeratin stain on H&E node-negative SLNs. IHC anal-sis was performed on all patients with nodal ITC detectednd on the majority (86%) of patients identified withodal MIC.For this analysis, data were reviewed focusing on patients

ith ITC and MIC found on pathologic evaluation, andetastases were reclassified by the 6th edition of the AJCCanual. An average of 2.1 SLNs was identified in the

atients in this study. Consistent with standard clinicalractice, the pathology is reported on a patient basis, basedn the most extensive disease found in any of the SLNs.atients listed on the pathology report as having only ITCsdentified or nodal metastases � 0.2 mm on H&E or IHCere classified as ITC. If patients were reported to haveicrometastases by H&E or IHC, and if the pathology

eport did not specify the size or did not specifically reportTCs, the patient was classified in the MIC group.

tatistical analysishe recurrence-free intervals7 for the SLN-negative (�),

TC, MIC, and SLN-positive (�) patients were evaluatedor distant metastases. Distant recurrence-free interval isefined as the interval between the SLNB (and definitiveperation) and distant recurrence or death from breast can-

er. Patients who did not have distant recurrences were

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335Vol. 208, No. 3, March 2009 Reed et al Isolated Tumor Cells in Sentinel Nodes

ensored at the time of their last followup. Patients whoied from unrelated causes were censored at death. Sevenatients in this study were lost to followup (mean 1-yearollowup after definitive operation). Kaplan-Meier curvesere used to estimate the distant recurrence-free interval

unctions for the four categories of patients according toheir SLN category: SLN (�), ITC, MIC, and SLN (�).he log-rank test was applied to compare the distant

ecurrence-free interval functions across the four categoriesf patients. The hazard of distant recurrence was assessednd compared between patient groups using the Cox re-ression model. The rate of distant recurrences was com-ared using the exact Fisher-Freeman-Halton test (r by contingency tables), and the Fisher’s exact test for 2 � 2ables. The logistic regression model was used to assesshether the SLN category correlated with whether or not

he ALND non-SLNs were positive versus negative. Alltatistical tests were done at the 0.05 level of significance.

ESULTSf the 1,259 patients, 893 (71%) were SLN (�), 25 (2%)

ad ITC, 57 (4%) had MIC, and 284 (23%) were SLN (�)Table 1). Of the 430 SLN (�) patients who underwent anLND, 26 patients (6%) had positive nonsentinel axillaryodes. Of the 243 SLN (�) patients who had an ALND,20 (49%) had additional positive nodes. None of the 13TC patients who underwent an ALND had additionalositive nodes. Forty-one of those with nodal MIC under-ent an ALND, with 11 (27%) having additional nodal

nvolvement.At a mean followup of 4.9 years, of the 1,259 study

atients, 122 (10%) had distant recurrence. The distantecurrence rates for SLN (�), ITC, MIC, and SLN (�)atients were 6%, 8%, 14%, and 21%, respectively (Table 1).igure 1 depicts the Kaplan-Meier curves used to estimatehe distant recurrence-free interval functions for the fourategories of patients according to their SLN status: SLN�), ITC, MIC, and SLN (�). There are evident differ-nces in distant recurrence experiences across these four

able 1. Recurrence Rates for Negative Sentinel Lymph Nodeymph Nodes

SLN statusPatient

(n � 1,2athology Size n

LN (�) 0 893LN ITC � 0.2 mm 25LN MIC � 0.2 mm to 2 mm 57LN (�) � 2 mm 284

LN, axillary lymph node; ALND, axillary lymph node dissection; ITC, iso

roups; p � 0.0001 (log-rank test). The hazard of distant c

ecurrence was 1.5 times higher in MIC patients versusLN (�) patients (CI 1.0 to 2.2; p � 0.02). Using theisher’s exact test, there was no significant difference in theroportion of patients with distant recurrence betweenhe SLN (�) and ITC categories (exact two-sided p � 0.65)r between patients with MIC and SLN (�) (exact two-ided p � 0.28), but there was a significant difference be-ween patients with negative SLNs and those with MICexact two-sided p � 0.02). There were no axillary recur-ences in the SLN (�), ITC, and MIC patients. The onlyour patients in the study with ALN recurrences were in theLN (�) group (4 of 284; 1.4%) and distant metastasesad also developed.Demographic data for each nodal grouping and the pa-

ients in whom recurrence developed are shown in Table 2.

igure 1. Kaplan-Meier curves to estimate the distant recurrence-ree interval functions for the four categories of patients accordingo their SLN category; SLN (�), ITC, MIC, and SLN (�). The log-rankest was applied to compare the distant recurrence-free intervalunctions across the four categories of patients. ITC, isolated tumor

olated Tumor Cells, Micrometastases, and Positive Sentinel

Patients with positivenonsentinel ALN/

patients with ALND, nDistant

recurrencen % n %

1 26/430 6 52 62 0/13 0 2 84 11/41 27 8 143 120/243 49 60 21

umor cells; MIC, micrometastases; SLN, sentinel lymph node.

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336 Reed et al Isolated Tumor Cells in Sentinel Nodes J Am Coll Surg

able 2. Baseline Characteristics and Distant Recurrence

haracteristic

SLN (�) ITC MIC SLN (�)

Total n Recurrence Total n Recurrence Total n Recurrence Total n Recurrence

n % n % n % n % n % n % n % n %

ace

African American 140 16 11 8 3 12 0 0 9 16 1 11 62 22 23 37

Non African American 753 84 41 5 22 88 2 9 48 84 7 15 222 78 37 17

Total 893 52 25 2 57 8 284 60

ge at diagnosis, y

� 50 249 28 14 6 7 28 1 14 23 40 6 26 118 42 35 30

� 50 644 72 38 6 18 72 1 6 34 60 2 6 166 58 25 15

Total 893 52 25 2 57 8 284 60

athology

Ductal 718 80 47 7 17 68 2 12 50 88 8 16 223 79 49 22

Lobular 90 10 4 4 4 16 0 0 2 4 0 0 37 13 5 14

Other 85 10 1 1 4 16 0 0 5 9 0 0 24 8 6 25

Total 893 52 25 2 57 8 284 60

umor size, cm

� 0.5 105 12 3 3 1 4 0 0 0 0 0 0 12 4 3 25

� 1 214 24 6 3 2 8 1 50 12 21 1 8 23 8 2 9

� 2 387 44 25 6 10 40 0 0 30 53 4 13 111 39 19 17

� 4 160 18 16 10 11 44 1 9 14 25 3 21 100 35 22 22

� 4 19 2 2 11 1 4 0 0 1 2 0 0 37 13 14 38

Total 885 52 25 2 57 8 283 60

otal positive nodes

0 866 97 49 6 25 100 2 8 0 0 0 0 0 0 0 0

1–3 25 3 3 12 0 0 0 0 53 93 7 13 201 71 27 13

� 3 2 0 0 0 0 0 0 0 4 7 1 25 83 29 33 40

Total 893 52 25 2 57 8 284 60

umor differentiation

Well 143 22 2 1 1 6 0 0 9 19 2 22 39 18 2 5

Moderate 282 43 11 4 5 29 0 0 28 60 5 18 89 42 15 17

Poor 237 36 31 13 11 65 2 18 10 21 1 10 85 40 30 35

Total 662 44 17 2 47 8 213 47

ymphatic or vascularinvasion

Yes 117 17 8 7 9 56 1 11 21 44 5 24 126 51 35 28

No 570 83 31 5 7 44 1 14 27 56 2 7 123 49 20 16

Total 687 39 16 2 48 7 249 55

strogen receptor

Positive 652 76 31 5 17 68 0 0 49 88 7 14 208 76 30 14

Negative 206 24 21 10 8 32 2 25 7 13 1 14 66 24 25 38

Total 858 52 25 2 56 8 274 55

rogestin receptor

Positive 545 64 24 4 15 60 0 0 43 77 6 14 175 64 23 13

Negative 311 36 28 9 10 40 2 20 13 23 2 15 98 36 31 32

Total 856 52 25 2 56 8 273 54

ormonal therapy

Yes 593 69 27 5 15 63 1 7 45 82 6 13 183 70 25 14

No 263 31 24 9 9 38 1 11 10 18 2 20 80 30 23 29

Total 856 51 24 2 55 8 263 48

adiation therapy

Yes 671 77 40 6 14 58 0 0 39 68 4 10 208 74 49 24

No 197 23 11 6 10 42 2 20 18 32 4 22 73 26 11 15

Total 868 51 24 2 57 8 281 60

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337Vol. 208, No. 3, March 2009 Reed et al Isolated Tumor Cells in Sentinel Nodes

significantly greater percentage of patients with SLNIC were 50 years old or younger and had lymphatic or

ascular invasion, as compared with the SLN (�) patientsp � 0.006 by chi-square analysis). Of the eight MIC pa-ients in whom distant recurrence developed, six patients,r 75%, were 50 years old or younger. Most (n � 7) ofhese recurrent patients had only one MIC-positive SLN;ne patient had four SLNs that were MIC positive. Sevenf the recurrent MIC patients underwent ALND, resultingn total positive node counts in each patient of 1 (n � 3), 2n � 1), 3 (n � 2) and 12 (n � 1), and an average of 3.3otal positive nodes (SLN � ALN). This differs from anverage of 1.5 total positive nodes in the nonrecurrent MICroup. The number of positive SLNs or total ALNs doesot statistically correlate with recurrence, but with onlyeven recurrences to date, this group is underpowered todequately test this relationship. Most of the patients with

IC SLNs, as shown in Table 2, received chemotherapy79%, n � 45), or radiation therapy (68%, n � 39); 53%f patients (n � 31) received both treatments. Ten percentf MIC patients who received both chemotherapy and ra-iation or radiation alone suffered recurrence with distantetastases, compared with 22% of MIC patients who did

ot receive these treatments. Of note, the number of recur-ences was low, and these differences were not statisticallyignificant. Both of the recurrent patients with ITC hadoorly differentiated, estrogen- and progestin-receptor-egative primary tumors, and both received chemotherapy.oth had undergone ALND with no additional positiveodes found.

ISCUSSIONncidence of nonsentinel node metastases inatients with isolated tumor cellsnd micrometastaseshe reported rate of finding positive higher echelon lymphodes in the presence of SLN ITC (5% to 16%) and MIC14% to 25%) (Table 3)8-13 varies. Gipponi and associates9

eported on 116 patients with SLN MIC and ALND andound that the chance of finding nonsentinel node metas-ases increased with increasing primary tumor size. Of per-

able 2. Continued

haracteristic

SLN (�) IT

Total n Recurrence Total n

n % n % n %

hemotherapy

Yes 384 44 37 10 21 88

No 479 56 15 3 3 13

Total 863 52 24

TC, isolated tumor cells; MIC, micrometastases; SLN, sentinel lymph node

aps more significant clinical value, van Rijk and cowork- m

rs10 found that patients with SLN MIC (19%) also hadigher echelon nodal metastases, resulting in a treatmenthange in 7%; patients with ITC (7%) had other nodaletastases but received no treatment change. In contrast toost studies that showed a decreased percentage of positive

igher echelon nodes in patients with SLN ITC comparedith MIC, Houvenaeghel and colleagues11 reported com-arable percentages (16% versus 14.3%). These resultsay not be consistent with results from other studies be-

ause the size of the micrometastases was only approxi-ated in the majority of study patients.In a metaanalysis of publications from 1998 to 2003 by

serni and coworkers,12 the weighted mean estimate ofonsentinel node metastases associated with MIC was0%, but dropped to 9% if the SLN was detected by IHCnly. In our study, 27% (11 of 41) of patients with MICad higher echelon lymph node metastases; none of theatients with ITC had additional positive nodes. The vari-tion in these studies may be from differences in the studyizes, patient clinical characteristics, and different tech-iques in pathologic evaluation of the SLN. A recent study

ndicated that the more precise definitions of SLN metas-ases, now in place with the 6th edition AJCC staging man-al, combined with a pathologist training program, result

n a reproducible nodal stage classification,14 so currentrospective studies may provide more consistent results.Many physicians are now using the Memorial Sloan-

ettering Cancer Center online nomogram to calculate therobability of finding additional positive nonsentinel

ymph nodes after a positive SLN biopsy to help determinehe need for an ALND. The nomogram uses factors such asatient characteristics, tumor pathology, and positive SLNharacteristics. The information it generates can be veryelpful in discussions with patients. The weakness of thisodel in patients with MIC is that the size of the sentinel

ode metastases is not included in the nomogram formula,nd there are considerable data showing this is a significantredictor of finding positive nonsentinel lymph nodes.15-18

n addition, the nomogram has not been reliably predictivef the likelihood of positive non-SLNs in patients with

MIC SLN (�)

currence Total n Recurrence Total n Recurrence

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0 12 21 1 8 39 14 4 10

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338 Reed et al Isolated Tumor Cells in Sentinel Nodes J Am Coll Surg

rognostic significance of isolated tumor cellsnd micrometastasesecause of the increasing use of SLNB, detection of ITCnd MIC in sentinel nodes is more frequently becoming aherapeutic dilemma. The prognostic significance and clin-cal relevance of these previously occult metastases areontroversial.20-28 Rutgers20 recently reviewed the variousiagnostic strategies, protocols, and reports of axillary re-urrences in the absence of ALND. He concluded thatxamination of SLNs for MIC should be restricted to re-earch studies, and he cautioned against clinical decision-aking in response to SLN ITC or MIC. Others with

imilar conclusions include Kahn and colleagues,21 whoeexamined 214 patients who were node negative by con-entional pathologic evaluation with IHC and additional&E staining. At a mean followup of 8 years, the study

ound that occult MIC (27 patients) was not significantlyssociated with a shortened disease-free interval or de-reased disease-free survival. Analysis of a single center par-icipating in our East Carolina University/Anne Arundel

edical Center trial found that the incidence of nonsenti-el node involvement was low in patients with only SLNIC (1 of 16; 6%) and concluded that MIC in the SLN

id not indicate clinically significant disease or call forLND.22 The difference in the single center experience

rom the multicenter analysis reported here is most likelyecause of the smaller patient subset analyzed, the shorterollowup (3 to 30 months), and the failure to distinguishTC from MIC.

In contrast, several studies, including that from Cotend colleagues,1 support the prognostic importance of ITCnd MIC.13,23-29 Susnik and associates23 reexamined theodes of 48 patients in whom distant metastases developedithin 15 years after operation and compared them to 48

ge-matched patients who were disease free for 15 years

able 3. Summary of References on the Number of Nonseells and Micrometastases in Sentinel Lymph Node

irst author Year

Patients withITC in SLN

and ALND, nPatients with metasta

in non-SLN, n

alhoun8 2005 61 3 (1 macro, 2 MICipponi9 2006

an Rijk10 2006 54 4 (2 macro, 2 MICouvenaeghel11 2006 187 30serni12* 2004 347† 38 on H&E � 10 on Iox13 2008 107 10 (9 macro, 1 MICurrent study 2008 13 0

Metaanalysis.ITC identified as � 2 mm by IHC only.LND, axillary lymph node dissection; H&E, hemotoxylin and eosin; IHC,icrometastases; SLN, sentinel lymph node.

fter operation. He concluded that the presence of MIC in a

LNs was significantly correlated with the occurrence ofistant metastasis in T1 breast cancer patients. The Inter-ational (Ludwig) Breast Cancer Study, one of the largesttudies of patients with nodal MIC described to date, re-orted that 83 patients with MIC had a worse disease-freend overall survival after 5 years median followup than didatients who were node negative on retrospective analysisnd serial sectioning.24 Alberti and coauthors25 reported onstudy of 702 node-negative patients whose nodes were

eexamined with step sectioning and IHC. The followupata of 8 years demonstrated that patients with ITC had an

ncreased risk for experiencing metastatic relapse. A recentetrospective search of the Surveillance Epidemiology andnd Results (SEER) database of cases between 1992 and003 concluded that nodal micrometastases carried a prog-osis intermediate to N0 and N1 disease, even after adjust-

ng for tumor- and patient-related factors.26 Finally, whilehis article was under preparation, Cox and colleagues13

eported a retrospective slide review of SLNs from 2,408atients, all of which had multiple sectioning, had under-one IHC evaluation, and were reclassified by the AJCCth edition manual. This study reported that SLN micro-etastases were a major indicator of poorer overall and

isease-free survival compared with that for node-negativeatients, but SLN ITCs were not predictive.In the prospective study reported here with a mean fol-

owup of 4.9 years, the hazard of distant recurrence was 1.5imes higher in patients with MIC versus SLN (�) (CI 1.0o 2.2 and p � 0.02). Longer term followup will be re-uired to determine if this difference between MIC andegative SLN is maintained. Longer followup will also de-ermine if nodal ITCs continue to clinically behave like0, or if recurrences within the ITC group will occur with

ncreased lead time. Our study was limited by the fact thatistopathologic analysis was not performed at a single site

l Lymph Node Metastases in Patients with Isolated Tumor

%

Patients withMIC in SLNand ALND, n

Patients with metastasesin non-SLN, n %

4.9116 16 (10 macro, 6 MIC) 13.8

7.4 106 20 (16 macro, 4 MIC) 18.916 301 43 14.3

11–14 789 156 on H&E � 39 on IHC 20–259 97† 15 (14 macro, 1 MIC) 160 41 11 (7 macro, 4 MIC) 27

nohistochemistry; ITC, isolated tumor cells; macro, macrometastases; MIC,

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339Vol. 208, No. 3, March 2009 Reed et al Isolated Tumor Cells in Sentinel Nodes

ion, because the trial was initiated with staging under theJCC 5th edition, it is possible that some of the patientsith ITCs may have been inappropriately classified in theIC group for this analysis. The major strength of our

tudy is that it is one of the few prospective datasets from aulticenter trial that is representative of the practices in

ommunity settings and academic centers. The definitivenswer about ITC, MIC, and the value of increased patho-ogic evaluation with IHC may become apparent when theomparison outcomes of the two arms of the National Sur-ical Adjuvant Breast Project protocol B32 are revealed,ecause the physicians were blinded to results of the IHCtaining. Although the volume of disease present in theentinel node is almost certainly prognostic, accurate de-ermination of that volume, and the exact threshold athich it no longer has clinical significance, remain elusive.e, and others, are investigating the molecular analysis of

LN by real time reverse transcriptase-polymerase chaineaction as a strategy to quantitate tumor burden in lymphodes and establish clinically appropriate significanthresholds.

Our data support the conclusion that having nodal MICs associated with more positive nonsentinel nodes and car-ies a worse prognosis. In view of the significant morbidityf an ALND after an SLNB, because the incidence ofymphedema is 19.1% versus 3.5% for patients undergoingLNB alone, physicians struggle to determine which pa-ients may benefit from an ALND.30 The question remains,oes completing an ALND on these patients lead to im-roved survival? Is the ALND for micrometastatic sentinelode disease only a prognostic indicator, or does surgicallyemoving nonsentinel node disease lead to improved out-omes? The American College of Surgeons Oncologyroup Z0011 study had sought to answer these questions,ut it closed because of poor accrual. Hopefully, in the nearuture, the prognostic assessment and treatment recom-endations currently derived from ALND findings might

e replaced by molecular evaluations on the SLN or therimary tumor. If this were shown to be the case, it could

ead to a decreased need for ALND.To conclude, significant controversy remains about

rognostic implications and appropriate surgical manage-ent of patients with ITC and MIC on SLNB. Results

rom our prospective study support the recent AJCC reclas-ifications and suggest that ALND is not necessary in pa-ients with ITC, because no patients having an ALND hadositive nonsentinel nodes. This study also suggests thatareful attention should be paid to patients with poor his-ologic characteristics, even in SLN-negative patients withTC. Patients with nodal MIC should be considered for

LND and more aggressive adjuvant therapy, because 27%

ad additional positive axillary nodes, and nodal MIC wereignificantly associated with an increased incidence of dis-ant recurrence.

uthor Contributions

tudy conception and design: Rosman, Verbanac, Cheng, Tafracquisition of data: Reed, Rosman, Verbanac, Mannie, Chengnalysis and interpretation of data: Reed, Rosman, Verbanac,

Chengrafting of manuscript: Reed, Rosman, Verbanacritical revision: Reed, Rosman, Verbanac, Mannie, Cheng,

Tafra

cknowledgment: We thank Emmanuel Zervos, MD, Eastarolina University, for review of the article, and acknowledge

he technical and statistical assistance and database manage-ent of Kristen Sawyer, MS, CCRA, and Maryann Moreland,A, Anne Arundel Medical Center; Diane Boyce, RN, C

ustus Min, MS, MD, Debra Peaden, CCRP, East Carolinaniversity; and Olga Goloubeva, PhD, Johns Hopkins Uni-

ersity. We also acknowledge the support of the East Carolinaniversity-Anne Arundel Medical Center Sentinel Nodetudy Group (Eastern Virginia University/Sentara Norfolkeneral Hospital, Norfolk, VA; Winchester Hospital,oburn, MA; Carteret Surgical, Morehead City NC; Martha

efferson Hospital, Charlottesville, VA; Alamance Regionaledical Center, Burlington, NC; Memorial Hospital, Mar-

insville, VA; Carolinas Medical Center, Charlotte, NC;oore Regional Hospital, Pinehurst, NC; Mercy Hospital,

ortland, ME; Breast Care Center of the Blue Ridge,oanoke, VA; Virginia Beach General Hospital, Virginiaeach, VA; Moses Cone Hospital, Greensboro, NC; Lewisale Clinic, Salem, VA; Winchester Medical Center, Win-

hester, Va).

EFERENCES

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