1. Role of Sentinel Lymph Node biopsy in head and neck cancer
David Timme, MD
Division of Otolaryngology,
Southern Illinois University

2. TOPICS Case Presentation Lymphatic Drainage History of neck dissection
Techniques of Sentinel Node Biopsy
Limitations
Histologic Evaluation
Role in Head/Neck Cancer
Directions for the Future

3. Case Presentation 53 yo male with history of oral tongue cancer
Treated R partial glossectomy, b/l selective neck dissections (1-3)
Recurrence of tumor at primary site
Radiographic, clinical N0 neck
HANOT recommendation for wide local excision of site of recurrence
How to address elective neck dissection in previously dissected neck

4. TOPICS Case Presentation Lymphatic Drainage History of neck dissection
Techniques of Sentinel Node Biopsy
Limitations
Histologic Evaluation
Role in Head/Neck Cancer
Directions for the Future

5. Lymphatic Drainage Pathways1
1622 Aselli observed draining lymphatics in dogs
1787 Cruikshank “The Anatomy of the Absorbing Vessels of the Human Body”
1932 Rouviere classification of cervical lymph nodes according to location
Memorial New York – described 7 levels

6. 2

7. Lymphatic Drainage Pathways
Nodal basins at risk according to location 4
Oral cavity/Oropharynx I-III
Laryngeal/Hypopharyngeal II-IV
Posterior scalp/suboccipital II-V
Thyroid II-IV, VI
Common patterns reflected
in NCCN clinical guidelines

8. Lymphatic Drainage Pathways 5

9. Lymphatic Drainage Pathways
More than one primary drainage location may be present
Head and neck melanoma has more primary nodal sites than other organ sites 6

10. Lymphatic Drainage Pathways
Superficial Drainage Patterns (Cadaveric Study) 7
Typically follow venous routes
Alternate patterns from one side to another
Lymphaticovenous shunt present
Anterior neck lymphatics
above platysma, upward to
mandible

11. Lymphatic Drainage Pathways
Certain tumors may have skip metastases
First drainage node may differ from expected location
Tumor size can alter lymphatic drainage
Previous resection, lymphadenectomy, or radiation can all cause changes in drainage patterns
Current standard of care is based upon probabilities

12. Basis of Sentinel Lymph Node8
“First draining lymph node to receive lymphatic drainage from a primary tumor of a specific site”
Concept that a tumor will have preferred nodal drainage basin, with a primary node
Seaman/Powers 1955 first echelon node, nodal basin with radioactive colloid gold
Gould 1960 labeled first-echelon node the “sentinel node”
Cabanas 1977 identified specific groin node in primary penile cancer
Morton 1992 demonstrated intraoperative mapping in humans with melanoma using dye

13. The Challenge
Nodal Basin
Ideal Model:9
Tumor
Sentinel Node

14. The Challenge Reality: Tumor Sentinel Node? Sentinel Node?

15. The Challenge Reality: UNPREDICTABLE Tumor Sentinel Node?

16. The Challenge
Analogy:
UNPREDICTABLE

17. TOPICS Case Presentation Lymphatic Drainage History of neck dissection
Techniques of Sentinel Node Biopsy
Limitations
Histologic Evaluation
Role in Head/Neck Cancer
Directions for the Future

18. History of Neck Dissection1
19th Century occasional resection of grossly involved lymph nodes
1885 Butlin – elective removal of nodes in tongue cancer
1900 MacKenzie “extirpation of larynx with ..lymphatics and glands… diseased or not”
1888 Jawdynski described radical en bloc neck dissection

19. History of Neck Dissection
1905 Crile 121 operations with illustrations of block resections of cervical lymph nodes
Introduction of radical neck dissection
Hayes Martin 1951 – removal of CN XI, IJ, SCM should be standard
Functional, or “modified radical neck dissection” emerged in the 1950s
1960 Ballantyne pioneered modified approach
Continued work to determine optimal level of appropriate dissection needed

20. Neck Dissection Balance
Need to remove gross disease
Lessen undue morbidity
Prophylaxis against future development of metastases
shoulder dysfunction, facial edema, carotid blowout
Improve Clinical Outcomes
Improve clinical outcomes

21. Role for Sentinel Lymph Node Biopsy
Potentially lessen morbidity of large surgical resection
Guide treatment approaches (further neck dissection, radiation therapy, etc)
Further research of drainage patterns
Prognosis
Detect earlier stage “micrometastases”

22. Challenges for SLN in the Head
High density of lymph nodes
Close proximity to primary tumor
Complex lymphatic pathways
Optimization of localization and imaging essential for success

23. TOPICS Case Presentation Lymphatic Drainage History of neck dissection
Techniques of Sentinel Node Biopsy
Limitations
Histologic Evaluation
Role in Head/Neck Cancer
Directions for the Future

24. Techniques of Sentinel Lymph Node Localization
Dye
Pre-operative dynamic scintigraphy
Planar imaging
SPECT/CT
Intraoperative static scintigraphy

25. Technique – Dye 9
Injection of Isosulfan blue dye submucously around tumor
Nodes stained blue in min after injection
Exposure of nodal basin
Removal of stained node

26. Dye Limitations Invasiveness of broad exposure
Dye spillage around tumor – obscure margins
0.7-2% risk anaphylaxis
Skin tattooing
Washout with delay
Bredell reported on indocyanin green fluorescence10
Similar limitations as with blue dye

27. Dye
Is Dye Necessary?
Clinical Guidelines suggest use of dye may be optional
Some advocate for triple technique
Shoaib – more nodes identified with scintigraphy/dye combo compared to blue dye25
5/13 with dye
12/13 with radioactive tracer
Shoaib – 2 tumor positive nodes identified with blue dye alone in series of 40 patients (combo approach)26

28. Radiolabeled Tracer11 Scintigraphy relies upon radioactive tracer
Ideal particle size 5-10nm – smaller particles may be taken into vascular system
Gold, iodine, Technetium have been used
99mTc attached to sulfur colloid or human albumin most commonly used tracer
Investigation into other agents
Lymphoseek – dextran based product, avg. size 5nm
Half life 6 hours
Radioactivity detected 3-6 hours after injection
Ideally surgery same day as injection

29. Lymphoscintigraphy
Radiolabeled colloid injection around tumor periphery
Gamma camera to visualize dynamic real-time flow to sentinel nodes
Static images in A-P/lateral views obtained
Marking site of localized “hot spot”on the skin
Need to keep patient in static positioning until marking

30. Lymphoscintigraphy

31. SPECT/CT scintigraphy 12
Use of CT scanners as opposed to planar imaging
Combination with single photon emission CT (SPECT)
Better resolution of nodes adjacent to primary tumor where “shine through” obscures
Better definition of nodes relative to anatomical landmarks
Improved attenuation and scatter of gamma rays improves localization

32. SPECT/CT13 9 studies looking at SPECT/CT in OSCC
7 compared against planar lymphoscintigraphy
All identified at least one additional lymph node
Largest studies, 34, 40 patients. Additional lymph nodes identified in 37%, 47% of patients
Occult metastases identified in additionally imaged nodes
Has not entered into official guidelines

33. SPECT/CT

34. Intraoperative static lymphoscintigraphy
Use of handheld gamma probe to identify node
Nodes with peak reading removed
Any adjacent nodes with >10% activity also removed
Confirmation of excised nodes for positive activity
Remaining bed should have less than 10% activity
SLN ranked according to activity uptake ex-vivo

36. TOPICS Case Presentation Lymphatic Drainage History of neck dissection
Techniques of Sentinel Node Biopsy
Limitations
Histologic Evaluation
Role in Head/Neck Cancer
Directions for the Future

37. Safety14
Pelvic lymphoscintigraphy contraindicated for pregnant women; no proscriptions for head/neck
Low dose for the staff
Fewer than 100 SLNB during gestation below radiation exposure limits
Breastfeeding should suspend feeding 24 hr following injection
May do lower dose same-day surgery protocol

38. Risks Similar to neck dissection
Injury to facial nerve, spinal accessory nerve
Injury to vascular structures
(Operative exposure is more limited)
Completion neck dissection is conducted in recently operated field

39. Morbidity15
QOL may be higher in Sentinel Node Biopsy compared to selective neck dissection
Improved swallowing
Better pain, tactile sensation
Better scar appearance
Improved shoulder constant score
Trend towards less edema

40. Primary Tumor Removal Remove tumor before or after SLN removal?
Guidelines advocate either
Removal of tumor can lessen shine-through
If dye used, increased time for washout

41. How Many Nodes How many nodes to remove?
Removal of strongest signal alone would miss some positive nodes
39% of tumor positive nodes were not strongest radioactivity
Advocate around 3 nodes removed
Rarely more than 5 SLN
Advocate removal of any suspicious nodes as well

42. Non-localization16
5-10%
Predictive factors (review of 121 patients, 12 unsuccessful)
Location, floor of mouth/anterior tongue
T stage (higher stage more unsuccesful)
Pre-operative lymphoscintigraphy negative

43. Non-localization
“Shine through” from primary tumor can obscure identification
Tumor filling a node, distorting architecture, could redirect lymphatic flow
Suspicious nodes should be removed for that reason
Tumor size can directly compress draining lymphatics

44. Non-Localization Technical Incompetence
Two groups of surgeons, less than 10 prior experiences and more experienced group
More successful SLN identification in experienced group
Familiarity with techniques and principles
Inherent difficulties in the head/neck

45. Effect of Prior Treatment on Location17
Chemoradiation may alter drainage pathways
13 patients with pre-therapy SPECT/CT
Adjuvant chemoradiation
Pre-operative SPECT/CT
Intraoperative gammaprobe guided neck dissection

46. Effect of Treatment on Location
6/13 identical SLN
4/13 more SLN
3/13 less SLN
Post-treatment tumor changes may alter how injection is administered, although attempted to control

47. TOPICS Case Presentation Lymphatic Drainage History of neck dissection
Techniques of Sentinel Node Biopsy
Limitations
Histologic Evaluation
Role in Head/Neck Cancer
Directions for the Future

48. Histopathologic Evaluation
Protocols for SLN evaluation differ from routine node
Routine lymph node
Longitudinal sectioning
H&E staining
May miss up to 21% of diseased nodes
Large volume of nodes sampled precludes detailed examination at this point

49. Histopathlogic Evaluation14
Nodes in formalin
Routine H&E staining
If negative, then serial sectioning 150μm
Reevaluation with H&E staining
If negative, immunocytochemistry with pancytokeratin antibody

50. Histopathologic Evaluation
Recording of status
Macrometastases
Micrometastases
Isolated Tumor Cells

51. Classification14

52. TOPICS Case Presentation Lymphatic Drainage History of neck dissection
Techniques
Limitations
Histologic Evaluation
Role in Head/Neck Cancers
Directions for the Future

53. Roles in Head Neck Cancer
Established roles in cutaneous melanoma
Merkel Cell Carcinoma
Investigational
Squamous Cell Carcinoma
Oral Cavity/Oropharynx
Other subsites
Thyroid Carcinoma

54. Melanoma18 No NCCN guidelines regarding SLN for mucosal melanoma
Guidelines exist for primary cutaneous melanoma
Higher chance of + SLN in thicker tumors
3-7% chance in tumors <1mm thick
Higher survival rates for early dissection after +SLNB compared to delayed dissection
Early stage lesions have not shown survival benefit with addition of SLN at this point

55. Melanoma Presence of any nodal disease classifies at least stage III
N1 and N2 disease can be further subclassified into a and b according to micro or macrometastases
Current guidelines stratify to clinical trial or completion lymphadenectomy pending SLN status

56. Melanoma

57. Merkel Cell Carcinoma19 Staging reflects micrometastases
Stage IIIa or IIIb depending on micro or macrometastases
Evaluation should include IHC for CK-20, and pancytokeratin

58. Clinical Practice Guidelines SCCA14
Joint Clinical Practice Guidelines
European Sentinel Node Biopsy Committee
European Assocation of Nuclear Medicine Oncology Committee
Annals of Surgical Oncology, 2009
Oral/Oropharyngeal Squamous Cell Carcinoma
T1/T2 disease

59. Indications14 N0 neck Fit enough to undergo neck dissection
Stage ipsilateral neck in unilateral primary tumor
Assess bilateral neck in primary tumor near or crossing midline
Assess contralateral neck in primary tumors near midline with ipsilateral N+ neck to determine need for b/l neck dissection
Fit enough to undergo neck dissection
Prior radiation/surgical neck treatment “routinely excluded”

60. 5 year European Trial20 134 patients 79 SLNB alone
55 SLN assisted neck dissection
Triple method of SLN identification
T1/T2 oral cavity cancers
93% success of identification of SLN
FOM location lowest rates of identification

61. 5 year European Trial N0 necks upstaged 34% of the time
No difference in percent from SLN alone or END assisted
5 year follow-up
SNB-END: 22/53 upstaged (one node in neck specimen, not SLN)
Sensitivity 96%
NPV 97%
SND alone: 20/72 upstaged
Overall sensitivity 91%, NPV 95%
False negative SND alone:5
4/5 FOM

62. Conclusions 5 year European
Need more validation with larger trials
Lending support to using SNB as a staging tool
Not recommended for FOM primary
No significant survival differences between groups

63. Brazilian Trial21 35 patients (50 necks) SNB biopsy with gamma probe
Lip, Oral Cavity, Larynx, Oropharynx
SLN followed by END
41 necks SLN negative
5% positive neck nodes
9 necks SLN positive
H&E negative necks
2 nodes SSS/IHC positive
NPV 95%

64. Swiss Single-Institution Trial22
Stoeckli cohort of 79 patients
T1/T2 oral cavity/oropharynx
Validation phase (28) and observational phase (51)
Pre-operative scintigraphy, SPECT/CT, gamma probe
Intraoperative frozen section, followed by SSS/IHC
28 had SNB in conjunction with END
100% NPV
51 had SNB, and END based on results
19 patients then had completion ND
2 (6%) patients with neg SLN had neck recurrence
83% NPV frozen; 94% NPV overall

65. Swiss Single Institution Trial Long-Term23
Significant differences for disease specific survival, and neck control rate between SN(+) and SN(-)
10% of SLN (-) developed neck recurrence

66. 24 Multi-institution 140 patient T1-2 Oral Cavity
Primary tumor resection, SLN biopsy, followed by completion ND
SLN and largest node of each level evaluated by SSS/IHC
28% had neck positive disease
21/41 positive nodes were the SLN

67. False negative rate 9.8% 96% NPV overall 10% tongue 25% FOM
0% other sites
For more experienced surgeons, and smaller lesions, 0%
96% NPV overall

68. Prognosis of Sentinel Node27
103 patients T1-2 oral/oropharyngeal SCC
IA cisplatin chemotherapy
9 had SLN+, therapeutic neck dissection
Observation time 6.7 years
No false negative recurrences in ipsilateral neck
SN + SN –
5 year overall 38% 85%
Disease Free 47% 74%
Locoregional recurrence 22% 11%

70. Supraglottic Laryngeal28
29 patients T1-T3 N0 neck (clinical and CT)
SLND followed by b/l SND (I-VI)
5 subsites (submucosa, four quadrants and center) endoscopically
99mTc-albumin nanocolloid
Laser transoral tumor resection
1-2 hours later hand held gamma probe
Skin overlying peak radioactivity marked

71. Supraglottic Laryngeal
Mean sentinel lymph nodes harvested: 3
22/95 SLN were positive
58 neck dissections, 1 positive node, SLN was also positive
Positive nodes identified in levels 2&3
Positive node from dissection pre-laryngeal

72. Supraglottic Laryngeal
Sensitivity 100%
Negative Predictive Value 100%
5 year disease free survival 75%

73. Conclusions
SLN addresses some of the challenges of complex head/neck lymphatic drainage
SLN biopsy a new technique in the development of neck dissection
Expect refinements and improvement in technique, potential locations
As surgeons develop more experience, can have even better success
NPV of a negative node has good correlation with a negative neck dissection
Anticipate a broader role in future staging
Will await future NCCN guidelines to become standard of care

74. Future Work Absence of studies in previously operated neck
Our example patient a good example of potential new role for SLN
2 level V nodes removed, neg with SSS
Large long term studies with comparison to gold-standard ND
As evidence accumulates, potential entry into NCCN guidelines for SCCA
Prognosis of micrometastases compared to macrometastases altering survival?
Early knowledge(frozen section) vs. definitive knowledge, (SSS/IHC/PCR)?

75. References
1. Ferlito, A., et al Neck Dissection: Then and now. Auris, Nasis, Larynx, 33:
2. Myers, et al. Cancer of the neck 4E, Fig 18-1, p In Thomas, YW.
3. Robbins, et al Archives of Otolaryngology, 134:
5. Thomas, YW Pathways for Cervical Metastases in Malignant Neoplasms of the Head and Neck Region. Clinical Anatomy, 25: 54-71
6. Reynolds, et al Head & Neck. New York Head and Neck Society
7. Pan, WR Lymphatic Drainage of the Superficial Tissues of the Head and Neck: Anatomical Study and Clinical Implications. Plastic and Reconstructive Surgery, 121:
8. El-Sayed, IH Sentinel Lymph Node Biopsy in Head and Neck Cancer. Otolaryngol Clin N Am. 38:
9. Kuriakose, MA Sentinel node biopsy in head and neck squamous cell carcinoma. Curr Opin Otol Head and Neck Surg. 17:
10. Bredell, MG Sentinel lymph node mapping by indocyanin gree fluorescence imaging in oropharyngeal cancer-preliminary experience. Head & Neck Oncol. 2: 31

76. References 2
11. Coughlin, A Oral Cavity Squamous Cell Carcinoma and the Clinically N0 Neck: The Past, Present, and Future of Sentinel Lymph Node Biopsy. Curr Oncol Rep. 12:
12. Vermeeren, L SPECT/CT for sentinel lymph node mapping in head and neck melanoma. Head&Neck. 33:1-6.
13. Stephan, HK SPECT/CT for Lymphatic Mapping of Sentinel Nodes in Early Squamous Cell Carcinoma of the Oral Cavity and Oropharynx.
14. Alkureishi, LWT Joint Practice Guidelines for Radionuclide Lymphoscintigraphy for Sentinel Node Localization in Oral/Oropharyngeal Squamous Cell Carcinoma. Ann Surg Oncol. 16:
15. Schiefke, F Function, postoperative morbidity, and quality of life after cervical sentinel node biopsy and after selective neck dissection. Head Neck 24:
16. Hornstra, MT Predictive Factors for Failure to Identify Sentinel Nodes in Head and Neck Squamous Cell Carcinoma. Head & Neck
17. Validity of Sentinel Lymph Node Detection Following Adjuvant Radiochemotherapy in Head and Neck Squamous Cell Carcinoma. Wagner, A., et al Technology in Cancer Research and Treatment, 6,
18. NCCN Guidelines Version Melanoma.
19. NCCN Guidelines Version Merkel Cell Carcinoma
20. Alkureishi, LWT Sentinel Node Biopsy in Head and Neck Squamous Cell Cancer: 5-Year Follow-up of a European Multicenter Trial. Ann Surg Oncol. 17:

77. References 3
21. Chones, CT Predictive Value of sentinel node biopsy in head and neck cancer. Acta Oto-Laryngologica. 128:
22. Stoeckli, SJ Sentinel Node Biopsy for Oral and Oropharyngeal Squamous Cell Carcinoma of the Head and Neck. Laryngoscope. 117:
23. Broglie, MA Long Term Experience in Sentinel Node Biopsy for Early Oral and Oropharyngeal Squamous Cell Carcinoma. Ann Surg Oncol
24. Civantos, FJ Sentinel Lymph Node Biopsy Accurately Stages the Regional Lymph Nodes for T1-T2Oral Squamous Cell Carcinomas: Results of a Prospective Multi-Institutional Trial. Journ Clinical Oncology: 29:
25. Shaib T, et al A suggested method for sentinel node biopsy in squamous cell carcinoma of the head and neck. Head Neck. 21:
26. Shoaib T The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck. Cancer 91:
27. Kovacs, AF Postive Sentinel Lymph Nodes are a Negative Prognostic Factor for Sruvival in T1-2 Oral/Oropharyngeal Cancer- A Long-Term Study of 103 patients. Annal Surg. Oncology. 16:
28. Lawson, G Reliability of Sentinel Node Technique in the Treatment of N0 Supraglottic Laryngeal Cancer. Laryngoscope, 120: