1. Sentinel Lymph Node Biopsy Breast Cancer
Dr. LAI, Eric C.H.
Department of Surgery
North District Hospital

2. Sentinel Lymph Node Biopsy Introduction & Background
Background information of Axillary lymph node dissection
Development of Sentinel lymph node biopsy

3. Sentinel Lymph Node Biopsy Introduction & Background
Axillary Lymph Node Dissection

4. Sentinel Lymph Node Biopsy Introduction & Background
Axillary lymph node dissection (ALND) – an integral part of breast cancer management since Halsted introduced radical mastectomy in the mid-1800s
After World War II, Waangensteen and others advocated removing the supraclavicular and internal mammary lymph nodes and the axillary nodes
Nowadays, ALND is a gold standard for assessment of lymph node status.
Recently, some have suggested that removing clinically normal axillary nodes is not therapeutic, and so is unnecessary

5. Sentinel Lymph Node Biopsy Introduction & Background
Role of Axillary lymph node dissection (ALND)
Accurate staging & prognostic information
Selection for adjuvant systemic therapy
Impact on survival (Controversial)

6. Sentinel Lymph Node Biopsy Introduction & Background
Axillary recurrence after ALND
0% to 2.1%
Acute complication rate (e.g. fluid collection, infection, pain)
20% to 30%
Chronic complication rate (e.g. lymphoedema) 20% to 30%

7. Sentinel Lymph Node Biopsy Introduction & Background
In fact, the majority (~ 70%) of women with clinically negative axilla (N0) will prove to be microscopically negative
With improvement in screening and diagnostic investigation, more and more small primary tumour detected.
More breast cancer patients today do not have lymph node metastases.

8. Sentinel Lymph Node Biopsy Introduction & Background
ALND offers no benefit for this group of patients, and may do harm
An accurate noninvasive techniques for assessment of axillary status is needed.

9. Sentinel Lymph Node Biopsy Introduction & Background
Clinical assessment
29-38% false negative rate
Radiographic methods (mammography, computed tomography, positron emission tomography)
10-30% false negative rate
Random sampling of axillary nodes
40% false negative rate
Only Level I lymph node dissection
10-15% false negative rate

10. Sentinel Lymph Node Biopsy Introduction & Background

11. Sentinel Lymph Node Biopsy Introduction & Background
Concept of Sentinel Lymph Node Biopsy
The first node in the regional nodal basin that drains a primary tumour, reflects the tumour status of the entire nodal basin

12. Sentinel Lymph Node Biopsy Introduction & Background
Advantage
Accurate assessment of axillary lymph node involvement
Minimal morbidity
Accuracy
Identification rates
False-negative rates

13. Sentinel Lymph Node Biopsy Introduction & Background
Patients
T1,2 primary tumour with N0

14. Sentinel Lymph Node Biopsy Introduction & Background
Using a radioactive material or a blue dye, and often both
Local injection is into the breast tissue
The material will migrate through the lymphatics of the breast to the first lymph node draining the tumour.
The node(s) are then identified by color or by a handheld gamma probe.
They are removed and examined microscopically for the presence of metastatic tumour cells, often by frozen section examination.

15. Sentinel Lymph Node Biopsy Introduction & Background
Since the histologic status of the sentinel node is thought to represent the status of the entire axillary node basin, failure to detect metastasis in the sentinel node accurately predicts the negativity of the remaining axillary nodes and mitigates the need for a more extensive axillary dissection.

16. Sentinel Lymph Node Biopsy Introduction & Background
In 1960, Gould et al. described sentinel lymph node biopsy in parotid carcinoma
Gould EA, Winship T, Philbin PH, et al. Cancer 1960;13:77-8
In 1977, Cabanas introduced the concept of the sentinel node in penile cancer
Cabanas RM. Cancer 1977;39:
In 1992, Morton et al. published a description of the SLND technique for clinical stage I cutaneous melanoma.
Morton DL, Wen DR, Wong JH, et al. Arch Surg. 1992;127:392-9
This technique was further validated by other investigators

17. Sentinel Lymph Node Biopsy Introduction & Background
In 1994, Giuliano et al. adopted the dye-directed SLND technique in melanoma (a cutaneous tumour system) for use in primary breast cancer (a parenchyma tumour system).
Giuliano AE, Kirgan DM, Guenther JM, et al. Ann Surg. 1994;220:
In 1997, Giuliano et al. refined the technique and patient selection, he had improved the results of SLND. (Identification rate – 93.5%; false negative -0%; accuracy -100%)
Giuliano AE, Jones RC, Brennan M, et al. J Clin Oncol. 1997;15:

18. Sentinel Lymph Node Biopsy Content
Accuracy
Technical aspects
Contraindication
Therapeutic relevance of micrometastases in sentinel lymph nodes
Management of nonsentinel axillary lymph node in women undergoing sentinel lymph node biopsy
Future development

19. Sentinel Lymph Node Biopsy Content
Accuracy

20. Sentinel Lymph Node Biopsy Accuracy
SN identification rate and accuracy improved with surgeon experience
The learning curve was around 30 cases
In experienced centre
Identification rate – 98 % - 100%
False negative rate - <5 %
Accuracy – 98 % %

21. Sentinel Lymph Node Biopsy Accuracy
Author
Number
Sentinel Node identification rate
False negative rate
Accuraacy
Giuliano 1994
174
66%
12%
96%
Giuliano 1997
107
94% 0%
100%
Guenther 1997
145
71%
10%
97%
Veronesi 1997
163
98% 5%
Borgstein 1998
104 2%
99%
Feldman 1999 75
93%
19%
Moffat 1999 70
Veronesi 1999
376 7%
Krag 2001 4%
Quan 2002
152
Albertini 1997 62
92%
O’Hea 1998 60
15%
95%
Molland 2000
103
85%
Nano 2002
328
87% 8%
Krag 1998
443
91%
11%
McMasters 2000
806
88%
Tafra 2001
535
13%
Bergkvist 2001
498
90%
n/a
Shivers 2002
426
86%
McMasters 2003
3975

22. Sentinel Lymph Node Biopsy Content
Technical Aspect

23. Sentinel Lymph Node Biopsy Technical aspects
Injection Method
Injection Agents
Timing of injection
Preoperative lymphosintigraphy

24. Sentinel Lymph Node Biopsy Technical aspects – Injection Methods
Three Methods
Peritumoural Injection
Dermal or Subdermal Injection
Subareola Injection

25. Sentinel Lymph Node Biopsy Technical aspect - Peritumoral Injection
Original method used
A logical choice of tracer injection site
The peritumoral lymphatics should connect to the axillary SLN draining that particular region of the breast

26. Sentinel Lymph Node Biopsy Technical aspect - Peritumoral Injection
Limitations
Difficult for injection in nonpalpable tumour or tumour with large biopsy cavities
Longer learning curve
“Shine through” effect (an intraparenchymal injection of radioactive colloid around in the upper outer quadrant of the breast will obscure an axillary SLN that is close to the injection site)

27. A rich lymphatic network is present in the skin of the breast
Sentinel Lymph Node Biopsy Technical aspect – Dermal/Subdermal Injection
The breast parenchyma and overlying skin arise together from embryonic ectoderm, leading to a common lymphatic system and perhaps to a common SLN
A rich lymphatic network is present in the skin of the breast
A higher percentage of tracer injected into the skin reaches the SLN
Identification much easier and more predictable

28. Accuracy was confirmed by validation and concordance studies
Sentinel Lymph Node Biopsy Technical aspect – Dermal/Subdermal Injection
Accuracy was confirmed by validation and concordance studies
Validation study (axillary LN dissection was performed after sentinel LN biopsy)
Concordance studies (one tracer was injected into the dermis, and the other tracer was injected in the peritumoural location)
Accuracy was comparable to those of peritumoral injection

29. Study First Author n Identification rate % False negative %
Sentinel Lymph Node Biopsy Technical aspect – Dermal/Subdermal Injection
Study
First Author n
Identification rate %
False negative %
Concordance rate %
Validation
McMasters
2001
511 98
6.5%
Veronesi
1997
163
4.7%
Boolbol
100 99
9.0%
Casalegno
2000
102 86
5.4%
Concordance
Linehan
1999
95%
Borgstein 33
100%

30. The SLN is “hotter” and easier to identify Rapid transit time
Sentinel Lymph Node Biopsy Technical aspect – Dermal/Subdermal Injection
Advantage
The SLN is “hotter” and easier to identify
Rapid transit time
(SLN biopsy can be performed mins. after skin injection compared with several hours after peritumoral injection)
3. Avoid the “shine through” problem

31. Sentinel Lymph Node Biopsy Technical aspect – Subareola Injection
Lymphatic drainage of the subareolar region mirrors that of the breast parenchyma
Accuracy was confirmed with validation and concordance studies also
Subareolar injection appears to improve SLN identification and to be at least as accurate as peritumoral injection

32. Sentinel Lymph Node Biopsy Technical aspect – Subareola Injection
Study
First Author n
Identification rate %
False negative %
Concordance rate %
Validation
McMasters
2001 85 99
5.9
Kern
1999 40 98
Smith
2000 19
100
Concordance
Bauer
245 96 90
Kimberg 68 94
Turtle
2002
159
Borgstein
130 95

33. Sentinel Lymph Node Biopsy Technical aspect – Subareola Injection
Advantage
Easier to learn & requires less expertise
Can be use in nonpalpable tumour
SN Identification much easier
Rapid transit time from nipple to axilla
Avoid the “shine-through” effect

34. Sentinel Lymph Node Biopsy Technical aspect – Injection Methods
Peritumoral, dermal or subdermal, and subareolar locations are all potential injection sites
Dermal or subdermal, and subareolar injection technique have distinct advantages and may shorten the learning curve

35. Sentinel Lymph Node Biopsy Technical aspect – Injection agent
Blue dye
Isosulfan blue dye
Methylene Blue
Patent Blue
Radioactive colloid
Technetium-99 sulfur colloid
Technetium-99 albumin

36. Sentinel Lymph Node Biopsy Technical aspect – Single agent versus Double agent Injection
Whether injection of a single agent (Blue dye or radioactive colloid) is as effective as the combination of 2 agents

37. McMaster and associates reported a series of 806 patients in 2000.
Sentinel Lymph Node Biopsy Technical aspect – Single agent versus Double agent Injection
McMaster and associates reported a series of 806 patients in 2000.
SLN identification rates were similar (single agent, 86%; dual agent, 90%)
Single agent use was associated with a significantly higher false negative rate (single agent, 11.8%; dual agent, 5.8%; p<0.05)
McMasters KM, Tuttle TM, Carlson DJ, et al. J Clin Oncol. 2000;18:2560-6

38. Sentinel Lymph Node Biopsy Technical aspect – Single agent versus Double agent Injection
Cody and associates reported that the combination of blue dye and radioactive colloid was complementary for SLN identification in 966 cases (Blue dye alone, 81%; radioactive colloid alone, 87%; both, 95%)
Cody HS, Fey J, Akhurst T, et al. Ann Surg Onc 2001;8:13-9

39. It is the most common approach currently used in clinical practice
Sentinel Lymph Node Biopsy Technical aspect – Single agent versus Double agent Injection
These data indicate that blue dye and radioactive colloid are complementary and might reduce false negative rate
It is the most common approach currently used in clinical practice

40. Sentinel Lymph Node Biopsy Technical aspect – Single agent versus Double agent Injection
The dual agent (radioactive colloid plus blue dye) technique is recommended to decrease false negative rates, especially when surgeons are just learning the procedure.

41. Sentinel Lymph Node Biopsy Technical aspect – Timing of Injection
Blue dye – Nearly all surgeons inject blue dye 5-15 minutes before the procedure
Radioactive colloid injection – The timing varies between surgeons and institutes
At least minutes is required for the colloid to localize in the SN

42. Sentinel Lymph Node Biopsy Technical aspect – Timing of Injection
Several studies have now demonstrated that it is feasible to wait up to 24 hours after injection of the radiocolloid to perform lymphatic mapping
Day before injection provides more flexibility for operation schedule

43. Improve identification rate and false negative rates
Sentinel Lymph Node Biopsy Technical aspect – Preoperative Lymphosintigraphy
Many early trials of lymphatic mapping for breast cancer incorporated breast lymphosintigraphy
2 main reasons for use:
Improve identification rate and false negative rates
Identify extra-axillary SLNs
Most centre do not use now

44. 2. Did not improve SLN identification rate or false negative rate
Sentinel Lymph Node Biopsy Technical aspect – Preoperative Lymphosintigraphy
Rarely identifies axillary SN that cannot be detected with the gamma probe
(More sensitive and specific hand held gamma probes became available; the technical details of the procedure were refined)
2. Did not improve SLN identification rate or false negative rate
3. Significantly increase the cost

45. Sentinel Lymph Node Biopsy Technical aspect – Preoperative Lymphosintigraphy
4. Role of internal mammary lymph node biopsy or dissection is not established
Incidence of isolated internal mammary metastases in the absence of axillary metastases
<3%

46. 5/36 (14%) was tumour positive
Sentinel Lymph Node Biopsy Technical aspect – Preoperative Lymphosintigraphy
Dupont and colleagues published the results of internal mammary biopsy in a series of 1470 patients undergoing SLN biopsy for breast cancer in 2001.
Radioactive internal mammary SLNs were identified and removed in 36 patients (2%)
5/36 (14%) was tumour positive
Only 2/5 had no axillary tumour positive SLNs
Dupont EL, Salud CJ, Peltz ES, et al. Am J Surg. 2001;182:321-4.

47. Breast cancer treatment was not altered based on the study also.
Sentinel Lymph Node Biopsy Technical aspect – Preoperative Lymphosintigraphy
Most of the internal mammary SLNs can be picked up by hand held gamma probe
Assuming that lymphosintigraphy was performed in all cases, 99.8% preoperative lymphsintigraphy were unnecessary
Breast cancer treatment was not altered based on the study also.

48. Preoperative lymphosintigraphy is costly and inconvenient
Sentinel Lymph Node Biopsy Technical aspect – Preoperative Lymphosintigraphy
Preoperative lymphosintigraphy is costly and inconvenient
It does not improve results
Removing internal mammary lymph nodes is unlikely to alter treatment or outcomes, and can add unnecessary morbidity

49. Sentinel Lymph Node Biopsy Content
Contraindication

50. Sentinel Lymph Node Biopsy Contraindication
Palpable lymph nodes
Locally advanced breast cancer
Multifocal breast cancer
Previous breast surgery
Previous radiation to the breast

51. Sentinel Lymph Node Biopsy Content
Therapeutic relevance of Micrometastases in Sentinel Lymph Nodes

52. Many believe that these immunometastases have no clinical significance
Sentinel Lymph Node Biopsy Therapeutic relevance of micrometastases in sentinel lymph nodes
Whether micrometastases identified by H & E and IHC have prognostic significance and should alter therapy
The general consensus is that micrometastases (<2 mm in diameter) identified by H & E staining have prognostic importance although not of the magnitude of macrometastases (>2 mm)
The significance of microscopic foci of epithelial cells in the SN that are only identified by IHC staining is unclear.
Many believe that these immunometastases have no clinical significance

53. Sentinel Lymph Node Biopsy Content
Management of Nonsentinel Lymph Node in Axilla

54. The long term sequelae of SLN biopsy remain to be defined
Sentinel Lymph Node Biopsy Management of Nonsentinel Lymph Node in Axilla
The long term sequelae of SLN biopsy remain to be defined
For SLN biopsy to replace ALND as a new standard of care, it is critical that axillary local control be at least comparable to that achieved after ALND
10 studies reported comparably good results in patients with a negative SLN biopsy and no ALND, with axillary local recurrence ranging from 0-1.4% at months of follow up.

55. Median follow-up (months) Axillary recurrence (%)
Sentinel Lymph Node Biopsy Management of Nonsentinel Lymph Node in Axilla Table. Axillary recurrence after negative SLN Biopsy & No ALND
Author
No.
Median follow-up (months)
Axillary recurrence (%)
Giuliano 2000 67 39
Veronesi 2001
285 14
Roumen 2001
100 24 1
Reitsamer 2002
116 22
Chung 2002
206 26
1.4
Veronesi 2003
167 49
Blanchard 2003
685 29
0.1
Winchester 2004
614 28
0.16
Janssen 2004
401
0.5
Naik 2004
2340 31
0.12

56. Positive sentinel lymph node = Axillary lymph node dissection
Sentinel Lymph Node Biopsy Management of Nonsentinel Lymph Node in Axilla
Positive sentinel lymph node = Axillary lymph node dissection
Whether ALND is required for all women with SN metastasis

57. Other studies found similar results
Sentinel Lymph Node Biopsy Management of Nonsentinel Lymph Node in Axilla
Surgical management of the axilla in patients with SN metastasis has been a subject of interest
It became clear that the SNs are the only involved nodes in many women with early stage breast cancer
Giuliano et al reported that the SNs were the only tumour positive nodes in 38-67% of patients with axillary metastases
Other studies found similar results

58. 4 reports regarding this subset of patients
Sentinel Lymph Node Biopsy Management of Nonsentinel Lymph Node in Axilla
4 reports regarding this subset of patients
Axillary local recurrence appears to be infrequent
Studies were performed to identify subset of women with very low risk of nonsentinel axillary lymph node involvement (e.g. tumour size, lymphovascular invasion, extracapsular invasion)
This group of women may not require ALND

59. Median follow-up (months) Axillary recurrence (%)
Sentinel Lymph Node Biopsy Management of Nonsentinel Lymph Node in Axilla Table. Axillary recurrence after positive SLN Biopsy & No ALND
Author
No.
Median follow-up (months)
Axillary recurrence (%)
Guenther 2003 46 32
Fant 2003 31 30
Winchester 2004 73 28
Naik 2004
210 25
1.4%

60. Sentinel Lymph Node Biopsy Content
Future Development

61. Sentinel Lymph Node Biopsy Future
Large scale RCT
ALND versus No ALND (for patients with negative sentinel lymph node)
ALND versus No ALND (for patients with low volume axillary disease)
Prognostic significance of micrometastasis identified by IHC

62. Sentinel Lymph Node Biopsy Conclusion
Sentinel lymph node biopsy accurately stages the axillary nodes in women with early stage breast cancer
Much less morbidity than axillary dissection