Role of Sentinel Lymph Node biopsy in head and neck cancer PowerPoint Presentation

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

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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

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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

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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

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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

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2

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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

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Lymphatic Drainage Pathways 5

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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

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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

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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

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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

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The Challenge Ideal Model:9 Tumor Sentinel Node Nodal Basin

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

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The Challenge Reality: UNPREDICTABLE Tumor Sentinel Node? Sentinel Node? Sentinel Node? Sentinel Node?

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The Challenge Analogy: UNPREDICTABLE

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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

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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

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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

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

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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”

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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

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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

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

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Technique – Dye 9 Injection of Isosulfan blue dye submucously around tumor Nodes stained blue in 15-45 min after injection Exposure of nodal basin Removal of stained node

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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

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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

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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

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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

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Lymphoscintigraphy

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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

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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

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SPECT/CT

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Histopathologic Evaluation Recording of status Macrometastases Micrometastases Isolated Tumor Cells

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Classification14

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

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

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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

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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

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Melanoma

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

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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

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Indications14 N0 neck 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”

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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

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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

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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

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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%

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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

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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

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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

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

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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%

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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

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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

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

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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

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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)?

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References 1. Ferlito, A., et al. 2006. Neck Dissection: Then and now. Auris, Nasis, Larynx, 33: 365-374. 2. Myers, et al. Cancer of the neck 4E, Fig 18-1, p. 408. In Thomas, YW. 3. Robbins, et al. 2008. Archives of Otolaryngology, 134: 536-538. 5. Thomas, YW. 2012. Pathways for Cervical Metastases in Malignant Neoplasms of the Head and Neck Region. Clinical Anatomy, 25: 54-71 6. Reynolds, et al. 2009. Head & Neck. New York Head and Neck Society 7. Pan, WR. 2008. Lymphatic Drainage of the Superficial Tissues of the Head and Neck: Anatomical Study and Clinical Implications. Plastic and Reconstructive Surgery, 121: 1614-1622. 8. El-Sayed, IH. 2005. Sentinel Lymph Node Biopsy in Head and Neck Cancer. Otolaryngol Clin N Am. 38: 145-160. 9. Kuriakose, MA. 2009. Sentinel node biopsy in head and neck squamous cell carcinoma. Curr Opin Otol Head and Neck Surg. 17: 100-110 10. Bredell, MG. 2010. Sentinel lymph node mapping by indocyanin gree fluorescence imaging in oropharyngeal cancer-preliminary experience. Head & Neck Oncol. 2: 31

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References 2 11. Coughlin, A. 2010. Oral Cavity Squamous Cell Carcinoma and the Clinically N0 Neck: The Past, Present, and Future of Sentinel Lymph Node Biopsy. Curr Oncol Rep. 12: 129-135. 12. Vermeeren, L. 2011. SPECT/CT for sentinel lymph node mapping in head and neck melanoma. Head&Neck. 33:1-6. 13. Stephan, HK. 2011. SPECT/CT for Lymphatic Mapping of Sentinel Nodes in Early Squamous Cell Carcinoma of the Oral Cavity and Oropharynx. 14. Alkureishi, LWT. 2009. Joint Practice Guidelines for Radionuclide Lymphoscintigraphy for Sentinel Node Localization in Oral/Oropharyngeal Squamous Cell Carcinoma. Ann Surg Oncol. 16: 1319-3210. 15. Schiefke, F. 2009. Function, postoperative morbidity, and quality of life after cervical sentinel node biopsy and after selective neck dissection. Head Neck 24: 432-436. 16. Hornstra, MT. 2008. Predictive Factors for Failure to Identify Sentinel Nodes in Head and Neck Squamous Cell Carcinoma. Head & Neck. 858-862. 17. Validity of Sentinel Lymph Node Detection Following Adjuvant Radiochemotherapy in Head and Neck Squamous Cell Carcinoma. Wagner, A., et al. 2007. Technology in Cancer Research and Treatment, 6, 665-660. 18. NCCN Guidelines Version 3.2012 Melanoma. 19. NCCN Guidelines Version 3.2012 Merkel Cell Carcinoma 20. Alkureishi, LWT. 2010. Sentinel Node Biopsy in Head and Neck Squamous Cell Cancer: 5-Year Follow-up of a European Multicenter Trial. Ann Surg Oncol. 17: 2459-2464.

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References 3 21. Chones, CT. 2008. Predictive Value of sentinel node biopsy in head and neck cancer. Acta Oto-Laryngologica. 128:920-924. 22. Stoeckli, SJ. 2007. Sentinel Node Biopsy for Oral and Oropharyngeal Squamous Cell Carcinoma of the Head and Neck. Laryngoscope. 117: 1539-1551. 23. Broglie, MA. 2011. Long Term Experience in Sentinel Node Biopsy for Early Oral and Oropharyngeal Squamous Cell Carcinoma. Ann Surg Oncol. 18.2732-2738. 24. Civantos, FJ. 2010. 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: 1395-1400. 25. Shaib T, et al. 1999. A suggested method for sentinel node biopsy in squamous cell carcinoma of the head and neck. Head Neck. 21: 728-733. 26. Shoaib T. 2001 The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck. Cancer 91: 2077-2083. 27. Kovacs, AF. 2008. 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: 233-239. 28. Lawson, G. 2010. Reliability of Sentinel Node Technique in the Treatment of N0 Supraglottic Laryngeal Cancer. Laryngoscope, 120: 2213-2217

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