Embed Size (px)
Citation preview
Ic(iRrptIgpdirlaSr
Rnvchswet
mwmn1asolnlSdchipwlms
S
Missed Micrometastatic Disease in Breast Cancer
May Lynn Quan and Hiram S. Cody III
bttstAtolaJta
tclclmcsrdptabste
taspp
S
SC
n the era of sentinel lymph node (SLN) biopsy for breastancer, ultrastaging by enhanced pathologic techniquesserial sections and/or immunohistochemical [IHC] stain-ng) has become logistically feasible for the first time.etrospective studies suggest that SLN (and bone mar-ow) micrometastases detected by these methods arerognostically significant, but controversy still surroundshe significance of micrometastases detected only byHC, and especially of isolated tumor cells. This hetero-eneity among micrometastases may confound the inter-retation of current prospective clinical trials that aim toetermine their significance. A major challenge for future
nvestigations will be to determine if SLN and bone mar-ow micrometastases represent similar or distinct bio-ogic phenomena, and whether this distinction will haveny implications for treatment.emin Oncol 31:311-317. © 2004 Elsevier Inc. All rightseserved.
ECENT DECLINES in breast cancer mortal-ity have been attributed both to earlier diag-
osis and to the increasing use of systemic adju-ant therapies.1 As the surgical treatment of breastancer has become less radical, systemic treatmentas increased. Coincident with this increase, risktratification is more important than ever. Forhich patients will the benefit of systemic therapyxceed the risk, and for which patients does sys-emic therapy represent over treatment?
Axillary lymph node status remains the singleost powerful prognostic indicator in patientsith breast cancer,2,3 and the presence of nodaletastases remains a key factor in determining theeed for adjuvant therapy.4 Unfortunately, about5% to 30% of node-negative patients will relapsend ultimately die of their disease, prompting theearch for other variables that may predict a poorutcome. These include primary tumor size, histo-ogic grade, and lymphovascular invasion, butone of these has equalled the prognostic power of
ymph node status as an independent variable.5entinel lymph node (SLN) biopsy, a new stan-ard of care for axillary nodal staging in breastancer, allows the routine performance of en-anced pathologic techniques and has renewed
nterest in the identification and prognostic im-ortance of axillary micrometastases in patientsho are node-negative by conventional patho-
ogic techniques. Here we review the subject oficrometastases, and in particular their prognostic
ignificance, in breast cancer.
eminars in Oncology, Vol 31, No 3 (June), 2004: pp 311-317
DEFINITION OF MICROMETASTASES
The term “micrometastases” was coined in 1971y Huvos et al,6 who arbitrarily made the distinc-ion between “macrometastases” and “micrometas-ases” using a 2-mm size threshold. Micrometasta-es were defined as tumor deposits measuring lesshan 2 mm; macrometastases were those �2 mm.lthough other arbitrary definitions of microme-
astases have been proposed, including percentagef the lymph node area examined7 and depositsess than 1.3 mm,8 a size threshold of 2 mm wasdapted through the fifth revision of the Americanoint Committee on Cancer (AJCC) staging sys-em in 19979 and is now the most widely used andccepted clinical definition.
The ability of enhanced pathologic techniqueso detect increasingly smaller deposits of tumorells prompted Hermanek et al10 to propose aower size limit to micrometastases at 0.2 mm,alling smaller metastases less than 0.2 mm “iso-ated tumor cells” (ITC), and deposits 0.2 mm to 2m in size “micrometastases.” The argument for
reating a lower size distinction for micrometasta-es arises from the hypothesis that ITCs may rep-esent a displacement artifact of the biopsy proce-ure rather than an indicator of true metastaticotential, and that metastatic potential is limitedo those patients with larger nodal deposits.3 Therbitrary lower threshold of �0.2 mm was selectedy the task force revising the most recent AJCCtaging system, in an effort to reduce the likelihoodhat ITCs being recorded as micrometastases, and toliminate the need to estimate cell number counts.11
A differentiating feature between micrometas-ases and ITCs emphasized by Hermanek et al10
nd noted in the most recent AJCC staging revi-ion is “evidence of metastatic activity,” such asroliferation, stromal reaction, extravasation, orenetration of the lymphatic sinus wall.3 While
From the Breast Service, Department of Surgery, Memorialloan-Kettering Cancer Center, New York, NY.Address reprint requests to Hiram S. Cody III, MD, Breast
ervice, Department of Surgery, Memorial Sloan-Kettering Cancerenter, 1275 York Ave, New York, NY 10021.© 2004 Elsevier Inc. All rights reserved.0093-7754/04/3103-0011$30.00/0
doi:10.1053/j.seminoncol.2004.03.012311
nbmmlopsoisntnt
ms
macg
dpffcft
tasiot
312 QUAN AND CODY
ot exclusionary, these findings are more likely toe present in deposits greater than 0.2 mm, anday be more indicative of a clinically significantetastases that has arrested and implanted in the
ymph node than deposits �0.2 mm. One of thebjectives of the staging system revisions is torovide a classification system so future clinicaltudies evaluating the effect of size and the methodf detection of nodal metastases can be standard-zed. The sixth revision of the AJCC’s stagingystem reflects these advances in pathologic tech-ique by acknowledging the method of tumor de-ection using subscript notation (Table 1). Ofote, micrometastases 0.2 to 2 mm render a pa-ient stage II, while the detection of ITC does not.
DETECTION OF MICROMETASTASES
Standard evaluation of axillary nodes, as recom-ended by the College of American Pathologists,
Table 1. AJCC Sixth Edition Staging System
Pathologic (pN)*pNx regional lymph nodes canno
study)pN0 no regional lymph node met
isolated tumor cells (ITC)
Note: isolated tumor cells (ITC) are defined as single tumor celimmunohistochemistry (IHC) or molecular methods but wof malignant activity, eg, proliferation or stromal reaction
pN0(i) no regional lymph node metpN0(I�) no regional lymph node metastpN0(mol�) no regional lymph node met
polymerase reaction (RT”pN0(mol�) no regional metastasis histol
* Classification is based on axillary lymph node dissection with or wsentinel lymph node dissection without subsequent axillary lymph
pN1 metastases in 1 to 3 axillarydisease detected by sentin
pN1mic micrometastasis (greater thaStage
0 TisI T1a
IIA T0T1a
T2IIB T2
T3
hould consist of one or two sections through the m
iddle of each node, stained with hematoxylinnd eosin (H&E) and examined by light micros-opy.5 Tumor deposits measuring at least 1 mm orreater can be detected using this method.
The concept of “obscure” metastases was intro-uced by Saphir and Amromin12 in 1948 aftererforming additional serial sections on nodesound negative on routine examination. Theyound additional metastatic disease in 33% andoncluded that serial sectioning should be per-ormed routinely to accurately assess the true sta-us of the nodes.
Numerous studies since then have demonstratedhe inadequacy of single-section analysis to reli-bly determine the presence of metastases. Serialectioning (SS) followed by H&E staining canmprove the detection of metastases by 7% to 33%ver routine histology,13-16 prompting the viewhat SS should be adopted as the new routine
gic Nodal Classification for and N1 Disease
ssed (eg, previously removed, or not removed for pathologic
istologically, no additional examination for examination for
ll cell clusters not greater than 0.2 mm, usually detected only byy be verified on H&E stains. ITCs do not usually show evidence
istologically, negative IHClogically, positive IHC, no IHC, no IHC cluster greater than 0.2 mmistologically, negative molecular findings reverse-transcriptase
positive molecular findings (RT-PCR)
entinel lymph node dissection. Classification based solely onssection is designated (sn) for “sentinel node” eg, pN0(i�) (sn)
odes, and/or in internal mammary nodes with microscopicnode dissection but not clinically apparent
m, none greater than 2.0 mm)
M0 aincludes T1micM0M0 bincludes N1micM0M0M0M0
Patholo
t be asse
astases h
ls or smahich ma
astasis hasis histoastasis h-PCR)ogically,
ithout snode di
lymph nel lymphn 0.2 m
N0N0N1b
N1b
N0N1b
N0
ethod of evaluation. However, routine SS on
ammwtv
aeodafpge
(scyPbttfiPs
cbd(mtbfpwmafw
IGi
eiercoteEtptv
w7twsClto2ctcsoitwpmr
bfSrnstmfItH
c
MISSED MICROMETASTATIC DISEASE IN BREAST CANCER 313
xillarly lymph node dissection (ALND) speci-ens was never embraced on a large scale; thisethodology was both labor-intensive and costly,ith many studies suggesting that the identifica-
ion of micrometastases in fact heralded no ad-erse clinical sequelae.Immunohistochemistry (IHC) uses monoclonal
nd polyclonal antibodies to epithelial elements,nhancing the identification of cells that mighttherwise have been overlooked. IHC increasesetection rates by 9% to 31% over standard H&E,nd by an additional 10% to 20% above thoseound by SS.17-22 IHC is of particular benefit inatients with invasive lobular cancer, where sin-le-cell micrometastases missed with routine H&Evaluation are easily found by IHC.18,23
Reverse-transcriptase polymerase chain reactionRT-PCR) has enabled the detection of evenmaller tumor deposits, down to one metastaticell in a million lymphocytes,24,25 increasing theield of micrometastases by 15% to 40%.26 RT-CR studies in breast cancer are currently limitedy the lack of markers unique to breast cancer, byhe extreme sensitivity of the technique (andherefore the possibility of contamination arti-acts), and by the absence of histopathologic val-dation in patients with “positive” results, but RT-CR has exciting potential and remains theubject of active investigation.
CLINICAL SIGNIFICANCE OFMICROMETASTASES
The debate over the clinical significance of mi-rometastases in breast cancer is ongoing. A num-er of studies6,8,13,14,27 between 1970 and 1980emonstrated no difference in disease-free survivalDFS) or overall survival (OS) in patients withicrometastases compared with those who were
ruly node-negative, but these studies were limitedoth by small size (�100 patients) and by shortollow-up (�5 years). Among those studies com-rising with more than 100 patients (Table 2) andith more than 5 years of follow-up, a substantialajority demonstrate significantly decreased DFS
nd OS in patients with micrometastatic diseaseound by SS and/or IHC, compared with thoseho were truly node-negative.16,18-20,28
The most notable of these is Trial V of thenternational (Ludwig) Breast Cancer Studyroup, published in 1990.16 This was a random-
zed trial testing whether a single dose of periop- o
rative chemotherapy would affect DFS and/or OSn axillary node-negative women, and 921 wereligible for evaluation. Negative lymph nodes aseported by local pathologists were evaluated byentralized study pathologists using re-cuts of theriginal paraffin blocks. SS methodology was used,aking two sections from each of six levels withinach paraffin block, and staining with H&E.ighty-three of 921 patients (9%) were convertedo node-positive and at 5 years had a significantlyoorer DFS and OS compared to true node-nega-ive patients: 58% versus 74% (P � .003) and 79%ersus 88% (P � .002), respectively (Table 2).A 10-year follow-up study to the Ludwig trial
as reported in 1999 by Cote et al,23 evaluating36 specimens from the initial cohort of 921 pa-ients. The previously sectioned paraffin blocksere re-examined, comparing a single section
tained with IHC (anticytokeratins AE � 1 andAM 5 � 2) to 12 sections (two from each of six
evels) stained with H&E. As in the earlier study,he SS/H&E method found micrometastases in 7%f patients, and the detection rate was improved to0% with the addition of single-section IHC. Mi-rometastases detected by SS/H&E (and those de-ected by IHC) were again associated with de-reased DFS and OS. This margin was statisticallyignificant only in the SS/H&E group and, curi-usly, only in postmenopausal patients. Also ofnterest, the authors stratified by micrometastaticumor burden, and demonstrated poorer outcomesith increasing volume of micrometastasis; com-aring patients with no cells, 1 to 100 cells, andore than 100 cells, they observed 10-year DFS
ates of 63%, 57%, and 40%, respectively.SS of lymph nodes obtained during ALND is
oth labor-intensive and costly, and therefore noteasible in routine practice. The emergence ofLN biopsy over the last decade has promptedenewed interest in enhanced pathologic tech-iques and reactivated debate over the clinicalignificance of micrometastases. SLN biopsy re-rieves an average of two to three nodes, thoseost likely to contain metastases, and has made
easible the routine use of SS and/or IHC analysis.HC on SLN specimens has improved the detec-ion of metastases by 6% to 26% over standard&E staining.33-36
Aside from prognostication, there are otherlear advantages to enhanced pathologic analysis
36
f SLN. Turner et al have validated the SLN
htdmSpamah
dAtHfH1
catiAdSht
conpsSt
314 QUAN AND CODY
ypothesis by demonstrating that (1) micrometas-ases are not merely a byproduct of more sensitiveetection, and (2) the SLN is indeed the nodeost likely to be positive; among patients whoseLNs were negative by both routine and enhancedathology, only one of 1,087 (0.09%) non-SLNsnalyzed by an identical method proved to containetastasis. Thus, axillary metastases do not occur
t random and the SLN is the node most likely toarbor disease.In addition, enhanced pathology allows the pre-
iction of non-SLN metastasis. CompletionLND is standard therapy for SLN-positive pa-
ients, 30% to 50% of whom will have additional&E-positive metastases in the non-SLNs. Even
or patients whose SLNs are positive only on IHC,&E-positive non-SLN metastasis are found in
37-39
Table 2. Summary of Studies Evaluating Presence of Micr
Author NSerial
SectionDetectionMethod
Axillary nodes*Huvos et al6 208 No H&EAttiyeh et al27 105 No H&EBlack et al7 172 — H&ERosen et al29 147 No H&EWilkinson et al15 525 Yes H&ETrojani et al18 150 No IHFriedman et al31 456 Yes H&ELudwig group16 921 Yes H&ENeville et al30 921 Yes H&Ede Mascarel et al19 336 Yes IHCHainsworth et al32 343 Yes IHCNasser et al20 159 Yes H&E, IHCMcGuckin et al22 208 Yes H&E, IHCCote et al23 736 Yes IHC
Bone marrow AntibodyMansi et al43 350 Anti-EMADiel et al44 727 ZE11Braun et al45 552 A45B/B3Gebauer et al46 393 —Solomayer et al47 727 —
BloodKrag et al48 21 9184, 9187Beitsch et al49 34 EPCAM
Abbreviations: DFS, disease-free survival; OS, overall survival; Hsignificant.
* Includes only studies with �100 patients.
0% to 16% of cases. A number of studies t
ombine variables (including tumor characteristicsnd size of micrometastasis) in an effort to predicthe likelihood of non-SLN metastasis37,40 anddentify a subset of SLN-positive patients in whomLND may not be required. We have recently
evised a nomogram to predict the risk on non-LN metastasis, drawing on the results of en-anced pathology as well as seven other his-opathologic features.41
No prospective trials to date show poorer out-omes in patients with axillary nodes positive onlyn IHC. Tan et al42 have reanalyzed the lymphode tissue blocks in 369 “node-negative” patientsreviously treated at our institution with radicalurgery and no systemic therapy, using our currentLN pathology protocol. They demonstrated thathe 18-year DFS of IHC-positive patients was in-
tases in Axillary Lymph Nodes, Bone Marrow, and Blood
% Positiveicrometases
Follow-up(yr) DFS OS
— 8 NS NS— 14 NS NS7.5 3 NS NS— 10 NS P � 0.01
17 15 NS NS14 10 P � .0025 P � .029 10 P � .059 5 P � .003 P � .0029 6 P � .0008 P � .00097 7 P � .005 P � .037
12 6 P � .05 NS31 11 P � .02 P � .0725 5 P � .021 P � .00720 12 P � .01 P � .003
25 6 P � .005 P � .00543 3 P � .001 P � .00136 3 P � .001 P � .00142 6 P � .006 P � .065— 6 P � .001 P � .005
95 — —97 — —
matoxylin & eosin staining; IHC, immunohistochemistry; NS, not
ometas
M
&E, he
ermediate between that of those who were truly
“oA(SbajtbmtlAmdst
ibltdpcigtd
ctpntfaofotttosfTw
optmp(cotstft
cpactwlapn
mtlotgbfamtoloitihct
i
MISSED MICROMETASTATIC DISEASE IN BREAST CANCER 315
truly node-negative” and those who were positiven H&E. Trials currently accruing include themerican College of Surgeons Oncology Group
ACOSOG) Z0010, an observational study ofLN biopsy in which investigators and patients arelinded to the results of IHC analysis of the SLNnd bone marrow, and the National Surgical Ad-uvant Breast and Bowel Project (NSABP)-32rial, a randomized trial of SLN biopsy with similarlinding to the results of IHC. Both aim to deter-ine the significance of IHC-detected microme-
astases in patients treated by conventional patho-ogic criteria. Pending these results, the sixthJCC staging system classifies micrometastases 0.2m to 2 mm as N1a disease, while smaller tumor
eposits detected by any other means are given N0tatus with notation of positivity for documenta-ion only.
MICROMETASTASES TO OTHER SITES
Micrometastatic disease has also been detectedn the bone marrow and blood of patients withreast cancer (Table 2). In a recent review of theiterature on studies of bone marrow micrometas-ases by Ozbas et al,50 micrometastatic cells wereetected in the bone marrow of breast canceratients (using various IHC methods) in 27% ofases (range, 1% to 48%). Despite wide variationn method of detection, heterogeneous patientroups, and short follow-up, there is fairly consis-ent evidence that bone marrow micrometastaseso correlate with poorer prognosis.Diel et al44 reported on 727 patients with breast
ancer and (using a monoclonal antibody) foundumor cells in the bone marrow of 43%. Theresence of tumor cells correlated with axillaryode status, tumor size, and histologic grade. In-erestingly, 31% of node-negative patients wereound to have tumor cells, suggesting cancer cellsre shed early in the stages of breast cancer devel-pment. On multivariate analysis at 36 months’ollow-up, the independent prognostic significancef occult bone marrow metastases was comparableo that of positive axillary nodes, and exceededhat of other histopathologic parameters. The au-hors emphasize in particular the significance ofccult bone marrow metastases for patients withmall, node-negative tumors, and a recent 6-yearollow-up is consistent with their earlier findings.47
he ACOSOG Z0010 trial, now fully accrued,
ill address the same issue. cA few small studies have evaluated the presencef micrometastases in the blood of breast canceratients (Table 2), and found tumor cells in 75%o 100% of patients with both early stage andetastatic breast cancer. Krag et al48 performed a
ilot study in 19 patients with early-stage diseaseusing an immunomagnetic method), and foundancer cells in the blood of 95% of patients pre-peratively and 30% postoperatively, suggestinghat some proportion blood-borne tumor cells arehed by the intact primary tumor but that persis-ent disease (at local or distant sites) may accountor the remainder. Further research is ongoing inhis exciting arena.
SUMMARY
The status of the axillary nodes is unable toompletely predict outcome in a significant pro-ortion of breast cancer patients. The studiesbove suggest that (1) micrometastases in breastancer are frequent, even in the setting of conven-ionally “node-negative” disease; (2) each patientith micrometastases has some combination of
ymph node, bone marrow, or blood-borne disease;nd (3) patients without micrometastases have arognosis better than that of historic norms forode-negative breast cancer.Regarding the first observation, the literature onicrometastases confirms the clinical intuition
hat subclinical metastatic disease is present in ateast some proportion of breast cancers at the timef diagnosis. The second observation has implica-ions that are both biologic and clinical. The de-ree to which lymph node, bone marrow, andlood-borne metastases represent similar (or dif-erent) biologic phenomena is unknown. The rel-tive frequency of each possible combination oficrometastatic sites is also unknown (Fig 1), as is
heir prognostic significance. Regarding the thirdbservation, the absence of micrometastases is ateast as important as their presence. The objectivef finding micrometastases is to identify patients atncreased risk who could benefit from systemicreatment, while the absence of micrometastasesdentifies patients at decreased risk (relative toistoric norms for node-negative disease based ononventional histopathology), for whom systemicherapy might represent over treatment.
The surgical therapy of breast cancer has movedn recent decades from an era of radicalism to
onservatism. In distinction, medical therapy has
penwibtt
UJ
itA2
Ac
cr
fC9
mA
os
si
AR
Ua
J2
m
1
ll
aCm
Pt
tc
tDc
stl
nP
tnv
ca
naG
omc
bp
a
bbcdtseto
316 QUAN AND CODY
aradoxically become more radical, expanding toncompass even the majority of women withode-negative disease, relatively few of whomould be expected to benefit. Further work to
dentify and characterize the presence (or absence)reast cancer micrometastases offers the potentialo reverse this trend, and more precisely to matchhe treatment to the disease.
REFERENCES
1. Chu KC, Tarone RE, Kessler LG, et al: Recent trends in.S. breast cancer incidence, survival, and mortality rates.Natl Cancer Inst 88:1571-1579, 19962. Fisher ER, Costantino J, Fisher B, et al: Pathologic find-
ngs from the National Surgical Adjuvant Breast Project (pro-ocol 4). Discriminants for 15-year survival. National Surgicaldjuvant Breast and Bowel Project Investigators. Cancer 71:
141-2150, 19933. Singletary SE, Allred C, Ashley P, et al: Revision of themerican Joint Committee on Cancer staging system for breast
ancer. J Clin Oncol 20:3628-3636, 20024. Early Breast Cancer Trialists’ Collaborative Group: Poly-
hemotherapy for early breast cancer: An overview of theandomised trials. Lancet 352:930-942, 1998
5. Fitzgibbons PL, Page DL, Weaver D, et al: Prognosticactors in breast cancer. College of American Pathologistsonsensus Statement 1999. Arch Pathol Lab Med 124:966-78, 20006. Huvos AG, Hutter RV, Berg JW: Significance of axillaryacrometastases and micrometastases in mammary cancer.nn Surg 173:44-46, 19717. Black RB, Roberts MM, Stewart HJ, et al: The search for
ccult metastases in breast cancer: Does it add to established
Fig 1. Schematic representation of micrometastases in thelood, bone marrow, or axillary lymph nodes in patients withreast cancer. Each patient with micrometastasis has someombination of lymph node, bone marrow, and blood-borneisease, as diagrammed above. The degree to which each ofhese overlap is largely unknown. Major objectives for futuretudies will to determine whether each site represents differ-nt (or similar) biologic phenomena, and to determine bothhe frequency and the clinical significance of each combinationf sites.
taging methods? Aust NZ J Surg 50:574-579, 1980 c
8. Fisher ER, Swamidoss S, Lee CH, et al: Detection andignificance of occult axillary node metastases in patients withnvasive breast cancer. Cancer 42:2025-2031, 1978
9. Breast, in Fleming ID, Cooper JS, Henson DE, et al (eds):JCC Cancer Staging Manual. Philadelphia, PA, Lippincott-aven, 1997, pp 171-18010. Hermanek P, Hutter RV, Sobin LH, et al: Internationalnion Against Cancer. Classification of isolated tumor cells
nd micrometastasis. Cancer 86:2668-2673, 199911. Breast, in Greene FL, Page DL, Fleming ID, et al (eds):
CC Cancer Staging Manual. New York, NY, Springer-Verlag,002, pp 223-24012. Saphir O, Amromin GD: Obscure axillary lymph-nodeetastases in carcinoma of the breast. Cancer 238-241, 194713. Pickren JW: Significance of occult metastases. Cancer
4:1266-1271, 196114. Rosen PP, Saigo PE, Braun DW Jr, et al: Occult axillary
ymph node metastases from breast cancers with intramammaryymphatic tumor emboli. Am J Surg Pathol 6:639-641, 1982
15. Wilkinson EJ, Hause LL, Hoffman RG, et al: Occultxillary lymph node metastases in invasive breast carcinoma:haracteristics of the primary tumor and significance of theetastases. Pathol Annu 17:67-91, 198216. International (Ludwig) Breast Cancer Study Group:
rognostic importance of occult axillary lymph node microme-astases from breast cancers. Lancet 335:1565-1568, 1990
17. Wells CA, Heryet A, Brochier J, et al: The immunocy-ochemical detection of axillary micrometastases in breast can-er. Br J Cancer 50:193-197, 1984
18. Trojani M, de Mascarel I, Bonichon F, et al: Microme-astases to axillary lymph nodes from carcinoma of breast:etection by immunohistochemistry and prognostic signifi-
ance. Br J Cancer 55:303-306, 198719. de Mascarel I, Bonichon F, Coindre JM, et al: Prognostic
ignificance of breast cancer axillary lymph node micrometas-ases assessed by two special techniques: Reevaluation withonger follow-up. Br J Cancer 66:523-527, 1992
20. Nasser IA, Lee AK, Bosari S, et al: Occult axillary lymphode metastases in “node-negative” breast carcinoma. Humathol 24:950-957, 199321. Chen ZL, Wen DR, Coulson WF, et al: Occult metas-
ases in the axillary lymph nodes of patients with breast cancerode-negative by clinical and histologic examination and con-entional histology. Dis Markers 9:239-248, 199122. McGuckin MA, Cummings MC, Walsh MD, et al: Oc-
ult axillary node metastases in breast cancer: Their detectionnd prognostic significance. Br J Cancer 73:88-95, 1996
23. Cote RJ, Peterson HF, Chaiwun B, et al: Role of immu-ohistochemical detection of lymph-node metastases in man-gement of breast cancer. International Breast Cancer Studyroup. Lancet 354:896-900, 199924. Noguchi S, Aihara T, Nakamori S, et al: The detection
f breast carcinoma micrometastases in axillary lymph nodes byeans of reverse transcriptase-polymerase chain reaction. Can-
er 74:1595-1600, 199425. Schoenfeld A, Luqmani Y, Smith D, et al: Detection of
reast cancer micrometastases in axillary lymph nodes by usingolymerase chain reaction. Cancer Res 54:2986-2990, 199426. Siziopikou KP, Schnitt SJ, Connolly JL, et al: Detection
nd significance of occult axillary metastatic disease in breast
ancer patients. Breast J 5:221-229, 1999
mG
ml
ao
nO
ttc
ac
pc
tp
alb
lb
awC
fS
cc
vmn
nmn
tsA
bl
bnI
pw5
bsO
dbR
i
t2
m
MISSED MICROMETASTATIC DISEASE IN BREAST CANCER 317
27. Attiyeh FF, Jensen M, Huvos AG, et al: Axillary micro-etastasis and macrometastasis in carcinoma of the breast. Surgynecol Obstet 144:839-842, 197728. Dowlatshahi K, Fan M, Snider HC, et al: Lymph nodeicrometastases from breast carcinoma: Reviewing the di-
emma. Cancer 80:1188-1197, 199729. Rosen PP, Saigo PE, Braun DW, et al: Axillary micro-
nd macrometastases in breast cancer: Prognostic significancef tumor size. Ann Surg 194:585-591, 198130. Neville AM: Breast cancer micrometastases in lymph
odes and bone marrow are prognostically important. Annncol 2:13-14, 199131. Friedman S, Bertin F, Mouriesse H, et al: Importance of
umor cells in axillary node sinus margins (“clandestine” me-astases) discovered by serial sectioning in operable breast car-inoma. Acta Oncol 27:483-487, 1988
32. Hainsworth PJ, Tjandra JJ, Stillwell RG, et al: Detectionnd significance of occult metastases in node-negative breastancer. Br J Surg 80:459-463, 1993
33. Giuliano AE, Kirgan DM, Guenther JM, et al: Lym-hatic mapping and sentinel lymphadenectomy for breast can-er. Ann Surg 220:391-398, 1994
34. Motomura K, Komoike Y, Inaji H, et al: Multiple sec-ioning and immunohistochemical staining of sentinel nodes inatients with breast cancer. Br J Surg 89:1032-1034, 200235. Peley G, Toth J, Csuka, et al: Immunohistochemistry
nd reverse transcriptase polymerase chain reaction on sentinelymph nodes can improve the accuracy of nodal staging inreast cancer patients. Int J Biol Markers 16: 227-232, 200136. Turner RR, Ollila DW, Krasne DL, et al: Histopatho-
ogic validation of the sentinel lymph node hypothesis forreast carcinoma. Ann Surg 226:271-276, 199737. Turner RR, Chu KU, Qi K, et al: Pathologic features
ssociated with nonsentinel lymph node metastases in patientsith metastatic breast carcinoma in a sentinel lymph node.ancer 89:574-581, 200038. Hill AD, Tran KN, Akhurst T, et al: Lessons learned
rom 500 cases of lymphatic mapping for breast cancer. Annurg 229:528-535, 199939. Wong SL, Chao C, Edwards MJ, et al: The use of
ytokeratin staining in sentinel lymph node biopsy for breastancer. Am J Surg 182:330-334, 2001
40. Weiser MR, Montgomery LL, Tan LK, et al: Lympho-ascular invasion enhances the prediction of non-sentinel nodeetastases in breast cancer patients with positive sentinelodes. Ann Surg Oncol 8:145-149, 200141. Van Zee KJ, Manasseh D-ME, Bevilacqua JLB, et al: A
omogram for predicting the likelihood of additional nodaletastases in breast cancer patients with a positive sentinelode biopsy. Ann Surg Oncol (in press)42. Tan LK, Giri D, Panageas K, et al: Occult micrometas-
ases in axillary lymph nodes of breast cancer patients areignificant: a retrospective study with long-term follow-up. Procm Soc Clin Oncol 21:37a, 2002 (abstr)43. Mansi JL, Gogas H, Bliss JM, et al: Outcome of primary-
reast-cancer patients with micrometastases: A long-term fol-ow-up study. Lancet 354:197-202, 1999
44. Diel IJ, Kaufmann M, Costa SD, et al: Micrometastaticreast cancer cells in bone marrow at primary surgery: Prog-ostic value in comparison with nodal status. J Natl Cancernst 88:1652-1658, 1996
45. Braun S, Pantel K, Muller P, et al: Cytokeratin-ositive cells in the bone marrow and survival of patientsith stage I, II, or III breast cancer. N Engl J Med 342:525-33, 200046. Gebauer G, Fehm T, Merkle E, et al: Epithelial cells in
one marrow of breast cancer patients at time of primaryurgery: Clinical outcome during long-term follow-up. J Clinncol 19:3669-3674, 200147. Solomayer EF, Diel IJ, Salanti G, et al: Time indepen-
ence of the prognostic impact of tumor cell detection in theone marrow of primary breast cancer patients. Clin Canceres 7:4102-4108, 200148. Krag DN, Ashikaga T, Moss TJ, et al: Breast cancer cells
n the blood: A pilot study. Breast J 5:354-358, 199949. Beitsch PD, Clifford E: Detection of carcinoma cells in
he blood of breast cancer patients. Am J Surg 180:446-448,00050. Ozbas S, Dafydd H, Purushotham AD: Bone marrowicrometastasis in breast cancer. Br J Surg 90:290-301, 2003
