Download Prognostic importance of occult axillary lymph node

1565
CLINICAL PRACTICE
Prognostic importance of occult axillary lymph
micrometastases from breast
INTERNATIONAL
cancers
(LUDWIG) BREAST CANCER STUDY GROUP
Serial sectioning of ipsilateral axillary lymph nodes
judged to be disease-free after routine histological
examination revealed micrometastases in 83 (9%)
of 921 breast cancer subjects. These patients had a
disease-free
poorer
(p=0·003) and overall
(p=0·002) survival after 5 years’ median follow-up
than did patients whose nodes remained negative
on serial sectioning. The presence of axillary lymph
node micrometastases correlated with the
presence of vascular invasion and tumour size
and
(p<0&middot;0001
p=0&middot;02, respectively). The
of
occult
micrometastases remained
presence
statistically significant after adjusting for other
prognostic factors. The detection of these
micrometastases in lymph nodes may identify a
high risk "node-negative" population and should
be considered as part of the routine pathology
examination.
Introduction
In 1981 the Ludwig Breast Cancer Study Group started an
international trial (Trial V) in patients 65 years of age or less
with proven breast cancer with or without ipsilateral axillary
lymph node involvement and without detectable distant
metastases. One of the aims was to ascertain whether
chemotherapy given in the immediate postoperative period
influenced the outcome not only in node-positive patients
but also in those considered to be node-negative after
histological examination and staging by the local
pathologists. 1.2All pathological
node
material was reviewed centrally. One
aspect of the central review was to examine serial sections of
ipsilateral axillary nodes that were categorised as negative
after routine examination locally and centrally. 1275 patients
were classified as node-negative by routine examination,
and nodes of 921 of these were serially sectioned.
There have been several reports3-8 of a high incidence of
occult nodal disease on re-examination, usually on further
sectioning of the histological material. However, there is no
unanimity as to the prognostic significance of such occult,
especially micrometastatic, nodal disease.6-12 We describe
here our assessment of the prognostic importance of
lymph-node micrometastases.
Subjects and methods
All patients entered into trial V had their breast cancers removed by
either total mastectomy with axillary clearance or modified radical
mastectomy. To be eligible, patients must have had unilateral
disease of clinical stage Tla, T, T 2a’ T2b, or T 3a’ No or Nl, and
Mo according to the TNM classification.
Patients were randomised to one of three groups, two of which
received one cycle of perioperative chemotherapy (intravenous
cyclophosphamide, methotrexate, and 5-fluorouracil on days 1 and
8) starting within 36 h of mastectomy. Two-thirds of those classed
as node-negative by the local pathologist received perioperative
chemotherapy. All node-negative patients received no other
treatment. Two-thirds of node-positive patients also received
perioperative chemotherapy, half with no additional therapy
(perioperative alone) and half with six additional cycles of
chemotherapy
(perioperative
plus
conventionally-timed
chemotherapy). The group of node-positive patients that received
no perioperative chemotheapy received six cycles of conventionallytimed chemotherapy. The results at 42 months median follow-up of
the node-negative2 and node-positive1 groups have been reported
elsewhere.
The local
pathologist was responsible for the histological
surgical specimens. The tissues were fixed in
buffered formalin, embedded in paraffm, sectioned, and stained
with haematoxylin and eosin (H&E)
as a standard procedure. A
complete set of stained sections from the primary tumour (two
sections were taken at right angles to each other whenever possible),
the nipple, the remaining quadrants of the breast, and all lymph
nodes identified in the specimen was then sent to the Ludwig Breast
Cancer Study Group Coordinating Centre in Bem, Switzerland,
for review. According to the pathology protocol, all paraffin blocks
preparation
of
’Writing Committee: R. Bettelheim, K. N. Price, R D. Gelber, B. W. Davis,
M Castiglione, A. Goldhirsch, A. M. Neville Correspondence to Dr A.
Goldhirsch, International Breast Cancer Study Group, Konsumstrasse
13, 3007 Bern, Switzerland
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TABLE I-NODE STATUS CONVERSION AND EFFECT ON 5-YEAR
DISEASE-FREE SURVIVAL
Disease-free and (b) overall survival for 921 node-negative
breast cancer patients whose lymph nodes were serially
sectioned by the central review pathologist.
(a)
Survival for 83 patients who became node positive (occult micrometastatic deposits found by the review) compared with that for 838
patients who did not convert. Median follow - u for the study cohort is five
years.
*1 medullary, 1 papillary.
tPentumoral vascular/lymphatic
#NS= >0 05
invasion.
containing lymph nodes originally found to be free of tumour were
forwarded to Central Pathology Review for further study. When it
was the policy of the clinic to keep all paraffin blocks on file, stained
and/or unstained serial sections of such lymph nodes, cut as
described below, were submitted.
All the paraffin blocks containing lymph nodes from the cases
reported locally and centrally as node-negative were serially
sectioned at six levels, with six 3 [t sections being cut at each level. At
least ten sections between levels were cut for regular spacing and
then discarded. The six serial sections from each level were
mounted on glass slides; two at each level were stained with H&E
and examined by the Central Review pathologists. The remaining
four sections from each level were filed for future
immunohistological studies. The median number of nodes per
patient examined was 14. The number of node blocks prepared for
examination varied between 1 and 45 per patient; the average was
12.
Only the presence of tumour cells within the body of the lymph
node was accepted as a metastasis. Tumour emboli in the
subcapsular sinus or in any endothelial-lined space within the node
were noted but were not counted as a metastasis. However, it is
important to note that tumour cells were found within the substance
of the nodes on further examination in all the cases in which initially
only a subcapsular, sinusoidal, or vascular metastasis was noticed.
The breast cancers were classified histologically according to
conventional WHO criteria. Tumour size, the presence or absence
of peritumoral vascular invasion, and histological grade13 were
recorded. Carcinomas were classified as non-invasive, intraduct
with minimum stromal invasion, limited invasive (50% of the
tumour consisting of intraduct carcinoma), invasive ductal, invasive
lobular, mixed ductal and lobular, or those with pure special
features such as tubular, mucous, papillary, squamous, and
medullary carcinomas. If another histological type of cancer other
than lobular carcinoma was present as well as infiltrating duct
carcinomas, the tumour was placed in the invasive ductal category.
Differences in incidence of conversion (of node status from
negative to positive) according to patient characteristics were
evaluated using X2 tests, and log-rank tests were used for
comparisons of disease-free survival. Estimates of 5-year diseasefree survival and their standard errors were calculated by the
Kaplan-Meier method and Greenwood’s formula, respectively.
Cox proportional hazards regression models were used to evaluate
the results, with adjustment for various prognostic factors. The
median follow-up at the time of these analyses was 5 years. All
p-values were two-sided.
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Results
receptor
Material needed for central review was available from 1203
of 1275 cases classified as lymph node-negative. In 46 cases
sections already examined by the local pathologist contained
a tumour metastasis. Material from 921 of the remaining
1157 cases was serially sectioned; in the others serial sections
were not cut because the lymph node material was not
forwarded to the Central Review laboratory (219 patients) or
was misplaced in the Cental office (17). The 5-year
disease-free survival for the 921 cases serially sectioned was
the same as that for the 354 cases not assessed (72%).
Serial sectioning revealed occult micrometastatic deposits
in 83 (9%) of 921 patients (table I). Conversion was
commoner among patients with larger tumours (p
0 02),
those with peritumoral vascular invasion (p < 0-0001),
and
those less than 50 years old (p < 0-0001). Ductal and lobular
carcinomas were equally associated with the presence of
occult nodal micrometastases.
There was a definite outcome disadvantage for those who
converted to the node-positive classification in 5-year
disease-free survival (58% [SE 6] vs 74% [2], p = 0-003, fig
[a] and table l) and in overall survival (79% [5] vs 88% [1],
p =0002, fig [b]). The difference was most obvious among
postmenopausal patients and those with invasive ductal
carcinomas. The difference was also noted between the two
treatment
groups, especially among patients given
=
perioperative chemotherapy.
Adjustment in Cox proportional hazards regression
models for patient age, menopausal status, oestrogen
TABLE II-PERCENTAGE (SE) PATIENTS WITH FIVE-YEAR
DISEASE-FREE SURVIVAL BY TREATMENT AND NUMBER OF
POSITIVE NODES FOUND ON SERIAL SECTIONING COMPARED
WITH PATIENTS CLASSIFIED AS NODE POSITIVE BY LOCAL
PATHOLOGIST
Numbers of patients given
in
square brackets.
TABLE III-REPORTED FREQUENCY OF OCCULT AXILLARY NODE
MICROMETASTASES
*All these cases were infiltrating lobular carcinomas.
tDetected by immunohistochemical methods and not serial sectioning.
status,
tumour
vascular
size,
invasion,
histopathological grade, and adjuvant treatment showed a
correlation
of
nodal
significant
prognostically
micrometastatic involvement with treatment (p 0 02) and
histopathological grade (p = 0 05), and especially with the
presence of vascular invasion (p 0 00002) and tumour size
(p = 0-002).
Since the trial had a cohort of node-positive patients
treated with the same perioperative regimen,l a comparison
=
=
made with that group in table
was
11.
Most
(70/83)
of the
patients with conversion of node status had only one positive
node, whereas most (279/381) of those recognised to be node
positive initially by the local pathologists had more than one
involved node. Patients with one affected node had similar
prognosis whether the metastasis was found by serial
sectioning or by routine examination. The beneficial
influence of perioperative therapy was also evident. Too few
patients had more than one node involved for inferences to
be drawn about effect of multiple node involvement.
Discussion
The
proportion of patients in this study with occult
lymph-node micrometastases (9%) is lower than that in
most other reports (table ill), perhaps because fewer
sections
were
examined than in the other studies. We
expected occult disease to be of only microscopic
proportions but, as in another report,9 this was not always
We found more than one affected node in 13 of 83
a considerable part of the node was replaced
carcinomatous
by
deposits.
Not unexpectedly large tumour size and peritumoral
vascular invasion were more likely than other factors to be
associated with conversion. Only vascular invasion was of
relevance in another study,5 in which tumour size, location
in the breast, and grade showed no correlation. No specific
histological type of tumour was more likely than others to be
associated with occult disease in our study, although
papillary and infiltrating lobular carcinomas have been
reported to be frequent associations.9,1o
The serial sectioning of multiple axillary lymph nodes is a
time-consuming practice and should be confirmed to be of
prognostic value and therapeutic importance before being
recommended for routine use. Our finding that nodal
micrometastases confer a disease-free and overall survival
disadvantage accords with that reported by Friedman et al,8
but is at variance with that reached by others .4,6, ’7Our study
differed from the others in that it was prospectively planned
and included a large number of subjects who were recruited
to a single clinical trial in a short time (4 years).
Wilkinson et al9 noted that nodal metastases overlooked at
the initial examination but detected without further node
sectioning at a later review carried a poorer survival
prognosis than did disease detected after serial sectioning. In
our study micrometastases were detected simply by reexamination of the initial material for 46 patients; their
prognosis (61% [8] disease-free survival) was less
favourable than that for node-negative patients but was
similar to that for patients with metastases detected
serial
on
sectioning. Among those who used
immunohistochemical methods to detect occult nodal
metastases without recourse to serial sectioning, Trojani et
allO,l1 reported that nodal micrometastases were associated
with higher recurrence and poorer survival rates.
Thus, from the most recent and present data, detection of
occult metastatic disease in the axillary nodes is important
the
case.
cases, and in 12
1568
since
it
carries a poorer prognosis. Perioperative
chemotherapy for this group of patients gave an added
disease-free survival advantage, especially when only one
node was involved. The beneficial effect of this form of
therapy reported for 42 months’ follow-up for nodenegative disease is shown in this study to be maintained at 5
years.
The detection rate of occult nodal micrometastases in this
series (9%) is well short of the total percentage of
node-negative subjects who will relapse within 5 years of
surgical removal of the tumour. Accordingly, it may be
advisable to divide each axillary node into 2 mm slices, as
suggested by Wilkinson et al,9 and to stain the histological
sections by immunohistochemical methods. 14,15 Such an
approach, together with a search for marrow
micrometastasesl6-18 and measurement of functional
primary
tumour
properties (eg, growth factors, proto-
oncogenes, ploidy), may serve to identify those poor risk
patients in the "presumed node-negative" group. The
stained
pathological examination of a single H&E
section is probably no longer clinically tenable.
node
We thank the patients, the doctors, especially the pathologists, the nurses, the
data managers who made this research possible. We also acknowledge the
Ludwig Institute for Cancer Research who initiated the project and the Swiss
and the Ticino Cancer Leagues, the Swiss Group for Clinical and
Epidemiological Cancer Research (SAKK), and Frontier Science &
Technology Research Foundation for generous fmancial support to enable its
completion.
International Breast Cancer
Study Group: Participants and Authors
(Pathologists in bold type):
A. Goldhirsch, M. Castiglione (Study Coordinators), R. Bettelheim,
A. M. Neville, B. Davis, W. H. Hartmann (Study Pathologists), D. Zava,
S. Misteli: Operation Center, Bem, Switzerland.
R. Gelber (Study Statistician), K. Price, M. Zelen: Harvard School of
Public Health & Dana-Farber Cancer Institute, Boston, MA, USA.
M. Isley, M. Parsons, L. Szymoniak: Frontier Science & Technology
Research Foundation, Amherst NY, USA.
R. G. Kay, J. Probert, B. Mason, H. Wood, E. G. Gifford, J. F. Carter,
J. C. Gillman, J. Anderson, L. Yess, 1. M. Holdaway, G. C. Hitchcock, M.
Jagusch. Auckland Breast Cancer Study Group, Auckland, New Zealand.
G. Marini, E. Simoncini, P. Marpicati, U. Sartori, A. Bami, L. Morassi,
P. Grigolato, D. DiLorenzo, A. Albertini, G. Marinone, M. Zorzi. Spedali
Civili & Fondazione Beretta, Brescia, Italy.
A. Hacking, D. M. Dent, J. Terblanche, A. Tiltman, A. Gudgeon, E.
Dowdle, P. Palmer. Groote Schuur Hospital, Cape Town, Rep of South
Africa.
C. G. Schmidt, K. H&ouml;ftken, L. D. Leder, R. Callies, A. E. Schindler,
University of Essen, West German Tumor Center, Essen, Germany.
P. Faber, H. G. Schniirch, H. Bender, H. Bojar, University of
Diisseldorf, Dusseldorf, Germany.
C.-M. Rudenstam, J. Save-Soderbergh’, E. Cahlin, S. Nilsson, J.,
Fomander, H. Salander, Ch. Johnsen, 0. Ruusvik, G. Ostberg, L. Mattsson,
C. G. Backstrom, S. Bergegardh, G. Ekelund, Y. Hessman, 0. Nelzen, S.
Dahlin, G. Wallin, L. Ivarsson, 0. Thoren, L. Lundell, U. Ljungqvist. West
Swedish Breast Cancer Study Group, Goteborg, Sweden.
J. Lindtner, J. Novak, D. Erzen, M. Sencar, J. Cervek, 0. Cerar, B.
Stabuc, R. Golouh, J. Lamovec, J. Jancar, S. Sebek. The Institute of
Oncology, Ljublijana, Yugoslavia.
H. Cortes-Funes, F. Martinez-Tello, C. Mendiola, F. Cruz-Caro, M. L.
Larodera, F. Calero, A Suarez, F. Pastrana, S. Cruchaga, B. Rodriguez.
Madrid Breast Cancer Group, Madrid, Spain
J. Collins, R. Snyder, R. Bennett, W. 1. Burns, J. Forbes, J. Funder, T.
Gale, L. Harrison, S. Hart, V. Humenuik, P. Jeal, P. Kitchen, R. Lovell, R.
McLennan, R. Reed, I. Russell, M. Schwarz, L. Sisely, P. Williams, H.
Ritchie. Anti-Cancer Council of Victoria, Melbourne, Australia.
M. Byrne, P. M. Reynolds, H. J. Sheiner, S. Levitt, D. Kermode, K. B.
Shilkin, R. Hahnel, G. van Hazel. Sir Charles Gairdner Hospital, Nedlands,
Western Australia.
SAKK (Swiss Group for Clinical &
Switzerland:
Epidemiological
Cancer
K. Brunner, G. Locher, E. Dreher, K. Buser, K. Biirki, M. Walther,
Joss, H. Burgi, M. Spreng, U. Hermann: Inselspital, Bem.
H. J. Senn, W. F. Jungi, W. W. Rittmann, M. Stanisic, Th.
Hardmeier, K. Luscher, G. Delmore, U. M. Luthotf, U. Haller, 0.
Schildknecht: Kantonsspital, St. Gallen.
F. Cavalli, H. Neuenschwander, W. Muller, C. Sessa, P. Luscieti, E.
Passega, P. Rey, S. Martinoli, E. Pedrinis, M. Varini, G. Losa, M.
Ginier. Ospedale San Giovanni, Bellinzona.
J. P. Obrecht, F. Harder, H. Stamm, U. Laffer, A. C. Almendral, U.
Eppenberger, J. Torhorst. Kantonsspital, Basel.
P. Siegenthaler, V. Barrelet, R. P. Baumann. Hopital des Cadolles,
NeuchateL H. J. Schmid. Kantonsspital, Luzern.
P. Alberto, P. Schafer, F. Krauer, M. Aapro, R. Egeli, R. Megevand,
E. Jacot-des-Combes, A. Schindler, F. Misset. Hopital Cantonal,
Geneva.
S. Leyvraz, P. Anani, F. Gomez, D. Wellmann, G. Chapuis, P. De
Grandi, P. Raymond. Centre Hopitalier Universitaire, Lausanne.
W. Weber, G. Noseda. Swiss Cancer League, Bern.
M. N. H. Tattersall, A. Coates, D. Hedley, D. Raghavan, F. Niesche, R.
West, S. Renwick, J. Donovan, P. Duval, R. J. Simes, A. Ng, T. Foo, D.
Glenn, R. A. North, J. Beith, R. G. O’Connor, M. Rice, J. Grygiel, J. Stewart,
R. Sillar. Urnversity of Sydney and Royal Prince Alfred Hospital, Sydney,
Australia.
R.
Research),
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