Axillary Recurrences after Sentinel Node Surgery—Results over Ten Years in a University Hospital

doi:10.4236/jct.2012.325108

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Journal of Cancer Therapy, 2012, 3, 846-852

http://dx.doi.org/10.4236/jct.2012.325108 Published Online October 2012 (http://www.SciRP.org/journal/jct)

Axillary Recurrences after Sentinel Node Surgery—Results

over Ten Years in a University Hospital

Helle Eilertsen1, Ellen Schlichting2, Marianne Efskind Harr3, Daehoon Park4, Torill Sauer1,5,

Siri Larønningen6, Rolf Kaaresen1,2*

1Medical Faculty, University of Oslo, Oslo, Norway; 2Department of Breast and Endocrine Surgery, Oslo University Hospital, Oslo,

Norway; 3Department of Neurosurgery, Oslo University Hospital, Oslo, Norway; 4Department of Pathology, Vestre Viken Hospital,

Drammen, Norway; 5Department of Pathology, Oslo University Hospital, Oslo, Norway; 6Cancer Registry of Norway, Oslo, Norway.

Email: *[email protected]

Received July 10th, 2012; revised August 15th, 2012; accepted August 27th, 2012

ABSTRACT

Background: Sentinel node biopsy (SNB) was introduced at Ullevaal University Hospital in 2000. This article presents

results from the first ten years use of the method. Material and Methods: A prospective registration of 2762 patients

was made from 2000 through 2009. Results: The median follow-up time was 51 months. The overall detection rate was

93%. 36% of the patients with positive SNs had non-sentinel metastases. These were significantly associated with a

macrometastatic SN and a primary tumour > 20 mm. 18% of patients with sentinel metastasis ≤ 2 mm had non-sentinel

metastases. 14 patients with negative SN (0.7%) developed axillary recurrence. 32% with a preoperative diagnosis of

ductal carcinoma in situ (DCIS) were upstaged to infiltrating carcinoma on final histology. None of the patients with

pure DCIS had positive SNs. Conclusion: Few late events (0.7%) in SN negative axillas demonstrate the safety of the

technique.

Keywords: Breast Cancer; Ductal Carcinoma in Situ; Sentinel Node; Non-Sentinel Metastasis; Axillary Recurrence

1. Introduction

As one of the first hospitals in Norway, Ullevaal Univer-

sity Hospital introduced sentinel node biopsy (SNB) as a

routine method in March 2000.

Between 400 and 500 patients were diagnosed with

breast cancer in the hospital per year during the study

period.

We present the results from the first ten years using the

SNB technique with a particular focus on three aspects:

- Axillary recurrences in patients with negative SN in

the first operation;

- The correlation between size of SN metastasis and the

risk of metastasizing to non-SN lymph nodes;

- The role of SN biopsy in patients with a preoperative

diagnosis of ductal carcinoma in situ (DCIS).

2. Patients and Methods

Between March 2000 and December 2009, 2762 patients

(2751 women and 11 men) with breast cancer underwent

SNB at Ullevaal University Hospital. 36 patients had

bilateral surgery and thus 2798 SNBs were performed

during the study period. The median age was 58 years

(22 - 92). 85% of the patients had preoperative diagnosis

of DCIS or infiltrating carcinoma by either fine needle

aspiration cytology (FNAC) or core biopsy, the rest by

surgical biopsy.

2.1. Registration of Data

A prospective, scheme based registration was used. The

data was kept in an internal hospital database with the

acceptance from the relevant authorities.

2.2. Inclusion and Exclusion Criteria

For the first 5 years patients ≤ 75 year with a preopera-

tively estimated tumour size ≤ 3 cm were included. The

last 5 years also patients with tumours between 3 and 5

cm were included with no upper age limit.

The exclusion criteria for the entire period were pa-

tients with cytologically verified axillary metastases and

those who had preoperative chemotherapy. During the

first 5 years DCIS and multifocal disease were exclusion

criteria, but for the last 5 years multifocality and DCIS

grade III on cytology or histology were included.

2.3. Identification of the Sentinel Node

Both blue dye and radioactivity were used to identify the

*Corresponding author.

Axillary Recurrences after Sentinel Node Surgery—Results over Ten Years in a University Hospital 847

SN. For the first 6 years, blue dye (One ml patent blue

diluted to 5 ml with isotone saline) and radioactivity (80

mBq in 08 ml) were injected peritumourally. From Janu-

ary 2006 the injection was made periareolarly. Radioac-

tivity was injected the day before surgery, whereas blue

dye was injected after the patients were under general

anaesthesia.

A lymph node was defined as a SN if the radioactivity

was at least ten times the background activity, whereas

the degree of colour was determined by a subjective as-

sessment by the surgeon.

2.4. Histopathological Examination of Sentinel

Node

All sentinel nodes were intraoperatively sent to frozen

section examination. The nodes were bisected along the

longitudinal axis and 2 - 3 frozen sections were cut from

each cut surface. About 8 - 12 sections were examined

per lymph node. All SNs were later formalin fixated,

paraffin embedded and stained with hematoxylin-eosin

and examined as part of the final histological evaluation.

(Figure 1) In cases of doubt, immunohistochemical test-

ing was performed [1].

2.5. Axillary Lymph Node Dissection

Axillary lymph node dissection (ALND) was performed

if the SN was positive either intraoperatively or after

final histological assessment. In the case of a negative

SN intraoperatively, the patient was reoperated if final

histology found a metastasis. Patients found to have SNs

with isolated tumour cells (metastasis < 0.2 mm) did not

undergo ALND, according to the guidelines of the Nor-

wegian Breast Cancer Group (NBCG) [2].

2.6. Reevaluation of Positive SNs

Positive SNs were later re-examined and the largest di-

ameter of metastasis remeasured by an independent pa-

Figure 1. Hematoxylin and eosin stained sentinel node with

metastasis from an infiltrating ductal carcinoma, micro

papilary subtype.

thologist (DP) blinded for other data.

2.7. Definition of Axillary Recurrence

Axillary recurrence was defined as detection of cancer

cells in the axilla more than 120 days after the date of

primary axillary surgery. The reports of axillary recur-

rences were found by searching the patient records in the

hospital verified and supplemented by the Cancer Regis-

try of Norway.

2.8. Statistical Analysis

Comparison of data between groups was made using chi-

square test and Fisher exact test. Multivariable analyses

were made using a multiple logistic regression model. A

two-tailed p-value of 0.05 or less was considered statis-

tically significant. Analyses were performed using SPSS

version 18.0 (SPSS Inc., Chicago, Illinois, USA).

3. Results

Median follow-up time was 51 months (0 - 117). Histo-

pathological tumour characteristics are given in Table 1.

3.1. Detection of Sentinel Node

The detection rate for the entire period was 93% (95% CI

92 - 94). Peritumoural injection of blue dye and radioac-

tivity gave a detection rate of 90% (95% CI 88 - 91),

whereas the detection rate with periareolar injection was

96% (95% CI 95 - 97). There was a significant difference

in detection rate after change of injection site (p < 0.001).

A total of 30 surgeons did the SN procedures. Their

detection rate did not differ significantly when grouped

according to the number of procedures they performed

(Table 2).

On multivariable analysis, neither age, tumour grade

or tumour size was found to be significant factors in the

detection of SN.

A median value of 1 node [1-8] was retrieved during

the SNB.

27% of the patients in whom SN was not found, had a

metastasis to one or more axillary nodes. The median

value of metastatic nodes after ALND was 3 (range 1 -

15).

3.2. Positive Sentinel Nodes

A positive SN on final histopathological examination

was found in 620 (24%) of the 2586 patients where SN

was detected. The largest diameter of SN metastases in

each patient categorized in three groups is shown in Ta-

ble 3.

141 patients had an intraoperatively false negative SN

and were reoperated with ALND. The negative predict-

tive value of intraoperative SN assessment was 93%

Axillary Recurrences after Sentinel Node Surgery—Results over Ten Years in a University Hospital

848

Table 1. Tumour characteristics of 2798 breast cancer pa-

tients. Missing data given in numbers only. The percentages

show the distribution of the parameter s in known cases.

Median invasive tumour size

(n = 2476, missing 41) 15 mm (range 0.5 - 86)

Histological type (n = 2776)

Ductal 1507 (54%)

Lobular 220 (8%)

DCIS 246 (9%)

Ductal + DCIS 623 (22%)

Other 180 (7%)

Missing 22

Histological grading of

invasive ductal carcinomas

(n = 1499)

1 469 (31%)

2 695 (47%)

3 335 (22%)

Missing 8

Oestrogen receptor status:

(n = 2456)

Positive 2059 (84%)

Negative 397 (16%)

Missing 61

Progesterone receptor status

(n = 2444)

Positive 1662 (68%)

Negative 782 (32%)

Missing 73

Her2 status (n = 1459*)

Positive 138 (9%)

Negative 1321 (91%)

Missing 39

*The registration of Her2 started in 2004.

Table 2. Detection rate related to total number of sentinel

node (SN) procedure s done by each surgeon.

Total SN

procedures per

surgeon

≤30 >30 ≤ 100 >100 ≤ 400>400

Det. Rate

[95% CI]

91%

[86 - 95]

94%

[91 - 97]

92%

[91 - 94]

93%

[91 - 94]

(95% CI 92 - 94). Of the patients with an intraoperatively

false negative SN, 71% had micrometastasis ≤ 2 mm.

On multivariable analysis, tumour size > 20 mm had a

significant association to positive sentinel nodes (p <

0.001), whereas tumour grade and receptor status had no

significant correlation.

3.3. Non-SN Metastases in Patients with Positive

Of the patients with positive SN, 36% had metastasized

also to non-sentinel lymph nodes.

There was a significant difference in the share of

non-SN metastases in correlation with size of the SN

metastasis (p < 0.001) (Table 4).

A multivariable analysis comparing SN positive pa-

tients with and without non-sentinel metastasis, found

that the only other characteristic, apart from size of SN

metastasis, was size of primary tumour. A significant

difference was seen between patients with tumours

smaller than and larger than 20 mm (p = 0.013).

3.4. Positive Sentinel Node in Ductal Carcinoma

in Situ Grade III

There were 225 patients with DCIS grade III on either

FNAC or core biopsy. Of these, 72 (32%) had infiltrating

carcinoma on final histology. Of the 211 patients with a

preoperative DCIS grade III diagnosis that we have data

on, 23 had a positive SN (11%), 11 of which had micro-

metastasis ≤ 2 mm. None of the patients with DCIS on

final histology had a positive SN.

3.5. Axillary Recurrences in SN Negative

Patients

Of those with negative SN, axillary recurrence was seen

in 14 patients (0.7%). The median interval of months

between time of surgery and registered date of axillary

recurrence was 24 (range 4 - 34).

A comparison of tumour characteristics of patients

with and without axillary recurrences, showed significant

differences for grade 3 tumours (p = 0.012), but not for

age, size or receptor status (Table 5).

Ki67 expression was seen in 92% of the patients with

axillary recurrence.

Table 3. Largest diameter of sentinel node (SN) metastases.

Size ≤2 mm > 2 ≤ 5 mm>5 mm

Share of SN metastases

(n = 620, 16 missing ) 170 (28%) 158 (26%) 276 (46%)

Table 4. Share of non-sentinel node (SN) metastasis related

to size of sentinel node metastasis.

Size (mm) ≤2 >2 ≤ 5 >5

Non-SN metastasis

[95% CI] 17% [12 - 23] 33% [26 - 40] 49% [43 - 55]

Axillary Recurrences after Sentinel Node Surgery—Results over Ten Years in a University Hospital 849

Table 5. Tumour characteristics in patients with and with-

out axillary recurrence.

Patients with

negative SN,

n = 1966

Patients with axil-

lary recurrence,

n = 14

p-value

Median age

(years) 59 14 NS*

Grade 3 217/995 (22%)7/14 (50%) 0.012

Oestrogen receptor

negative 281/1667 (17%)4/12 (33%) NS*

Progesteron

receptor negative 544/1661 (33%)6/12 (50%) NS*

Median invasive

tumour size (mm) 14 13 NS*

*NS: Non significant.

4. Discussion

Our rate of axillary recurrences supports the conclusion

from other studies: A negative SN is a reliable indicator

of axillary status and omitting axillary dissection after

negative sentinel node biopsy is safe [9-14].

4.1. Detection Rate

Our overall detection rate is slightly lower than what is

reported in other studies [3-6], but meets the require-

ments set by NBCG. The significant difference in detec-

tion rate after change of injection site support the change

in guidelines made by NBCG [2] from peritumoral to

periareolar injection as the preferred method. As we

found no significant differences in identification rate

between the experienced and inexperienced surgeons, a

hypothesis that the detection rate was so low because of a

large number of inexperienced surgeons at our teaching

hospital failed. Further, no clinical or tumour characteris-

tics were found to be significant in detecting SN. This

suggests that the method is less dependent of the surgeon

and the patient population and more dependent on quali-

ties within the method itself. An explanation for the rela-

tively low detection rate might be our stringent definition

for a SN to have at least ten times the background radio-

activity. Most publications on the method does not define

this level and might have included nodes we excluded

due to too low levels of activity.

4.2. Non-Sentinel Node Metastases

Macrometastasis to SN and size of primary tumour are

significant predictors for the involvement of non-SN

metastasis. Similar findings have been reported in other

studies [6-8,15,16].

18% of our patients with a SN metastasis ≤ 2 mm had

further nodal involvement. A metaanalysis of 25 studies

found an incidence of further nodal involvement in 20%

of patients with micrometastasis or isolated tumour cells

to SN [17]. The literature has for years been contradict-

tory about micrometastases` influence on recurrence and

survival [7,9,18]. Guiliano et al. recently concluded in

their randomized controlled trial that ALND might no

longer be justified for women with small breast carcino-

mas and a positive SN as long as a set of specified adju-

vant therapies are given [19]. The Norwegian Breast

Cancer Group have decided that patients with SN metas-

tasis ≤ 2 mm should avoid having ALND if breast pre-

serving therapy including radiotherapy to the breast and

lower axilla is carried out [2]. Similar to Hulvat et al.

[20], we did not find any correlation between receptor

positivity and/or histology grade with either SN or non-

SN metastasis.

4.3. Sentinel Node Metastasis in Ductal

Carcinoma in Situ

The value of doing SNB in DCIS has been disputed;

some authors are in favour [10,11,21,22], others against

[9-11,15-19,21-25]. Most, however, agree that it should

be done in patients who undergo mastectomy, because

this eradicates the possibility to later perform SNB if

preoperative diagnosis of DCIS is changed to infiltrating

carcinoma [26-28].

None of the preoperative DCIS patients in our material,

who on final histology was found to have true DCIS had

positive SNs, whereas 11% of the patients that were up-

staged to infiltrating carcinoma did. Based on these re-

sults we find that omitting SNB in patients with pure

DCIS on final histology could be justified, whereas pa-

tients that on final histology have an infiltrating compo-

nent should undergo SNB. The large share of patients in

our material (32%) who were upstaged from a preopera-

tive diagnosis of DCIS grade III by FNAC or core biopsy

to infiltrating carcinoma on final histology, shows that

invasive foci are often overseen in the preoperative

evaluation.

Some studies [10,29,30] have looked at risk factors

among preoperative DCIS patients that can predict pres-

ence of an invasive component and thus who could bene-

fit from having SNB performed as part of the initial op-

eration. These studies have contradicting results and a

definite conclusion is thus not possible.

4.4. Axillary Recurrences

An axillary recurrence rate of 0.7% with a median follow

up time of 51 months is acceptable and in accordance

with the results from other studies. A recent study with a

median follow-up time similar to ours, found a recur-

rence rate of 0.7% [31], another reports an axillary re-

currence rate of 0.6% after a median follow up time of 37

months [32]. A systematic review and meta-analysis of

Axillary Recurrences after Sentinel Node Surgery—Results over Ten Years in a University Hospital

850

48 studies found a recurrence rate for axillary metastasis

in clinically node negative women with a primary nega-

tive SN of 0.3% after a median follow up time of 34

months [33].

Our results indicate that longer follow-up time does

not increase the rate of recurrence much, in accordance

with other studies which observe that the majority of

recurrences happens during the first two years after di-

agnosis [5,19,34].

Apart from a significant higher share of grade 3 tu-

mours, we found no other significant characteristics in

the axillary recurrence population. Similar results were

reported by Kiluk et al. [35] and Bergquist et al. [32].

However, we had very few cases of recurrences in each

risk category, and the lack of significant relation of re-

currence to the other risk factors may be due to the low

number (n = 14) and thus lack of statistical power.

One explanation of the low axillary recurrence rate

might be that we have a low-risk population with a high

percentage of good prognostic factors such as small tu-

mour size (median 15 mm), oestrogen (84%) and pro-

gesterone (68%) positivity and a low frequency of poor

prognostic factors, such as lymph node involvement

(24%) and Her2 positivity (9%) (Table 1). This selection

is probably explained by the introduction of mammog-

raphy screening for women aged 50 - 69 in the hospital’s

referral area in 1996, four years prior to the introduction

of the SN procedure.

5. Conclusions

Few recurrences (0.7%) in SN negative axillas demon-

strate the safety of the technique. Apart from a signifi-

cant higher share of grade 3 tumours, we found no other

significant characteristics in the axillary recurrence popu-

lation. The median time to recurrence was 24 months.

The rather high frequency of patients with non-SN

metastases, also in those with micrometastasis (18%),

shows that removal of SN alone might not be sufficient

for local control of the axilla if axillary x-ray treatment is

not included.

The SN procedure seems unnecessary in patients with

histology proven DCIS not undergoing mastectomy.

6. Acknowledgements

Assistance with the finding and verification of recur-

rences by Ann Helen Seglem and Monica Johansen,

Cancer Registry of Norway is acknowledged.

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