Title

Sentinel lymph node biopsy in oral and oropharyngeal squamous cell carcinoma - current status and unresolved challenges

Authors

Christina Bluemel1, MD, Domenico Rubello2, MD, Patrick M Colletti3, MD, Remco de Bree4, MD, Ken Herrmann1, MD

Affiliations

1 Department of Nuclear Medicine, University Hospital of Würzburg, Würzburg, Germany

2 Department of Nuclear Medicine-PET/CT Oncologic & Endocrine Sections, Rovigo Hospital, Rovigo, Italy

3 Department of Radiology, University of Southern California, Los Angeles, CA, USA

4 Department of Head and Neck Surgery, UMC Utrecht Cancer Center, Utrecht, The Netherlands

Short title

SLNB in OSCC- update

Corresponding author/ Reprint Requests

Christina Bluemel, MD

Department of Nuclear Medicine, University Hospital of Würzburg

Oberdürrbacher Str. 6, 97080 Würzburg, Germany

Tel.: +49-931-201-35983; Fax.: +49-931-201-635000; Email:

Supplementary table: Characteristics and key points of included original studies reporting on sentinel lymph node biopsy in oral/ oropharyngeal squamous cell carcinoma*#

authors / year / topic/ key point / patients’ characteristics / tracer / SLN detection / relevant results / key massage
Chaturvedi [7] / 2014 / US-guided FNAC and SLNB / 51 pts with T1 or T2 oral SCC / 99mTc- nanocolloid / one day protocol; pre-op: planar LSG (15 min and 1 h) and SPECT;
intra-op:γ-probe; / US-guided FNAC vs. SLNB
sens: 14 vs. 71%spec: 100 vs. 100%
ppv: 100 vs. 100%
npv: 77 vs. 90% / US-guided FNAC not accurate enough to detect occult metastases
Alkureishi [13] / 2010 / final results European multicenter trial – 5 year follow up / 134 pts with T1 or T2 HN SCC (mainly oral SCC) / 99mT-nanocolloid and blue dye / pre-op: LSG;
intra-op: blue dye and γ-probe; / overall id-rate: 93%;sens: 91%; npv: 95%;
FOM vs. others:
sens: 80 vs. 97%; npv: 88 vs. 98%; / SLNB reliable and reproducible; reduced id-rate, sens and npv in FOM tumors
Civantos [14] / 2010 / final results ACOSOG multicenter trial / 140 pts with T1 or T2 oral SCC / 99mTc-sulphur colloids / pre-op: LSG
intra-op: γ-probe; / mean number of SLN per patient: 3;
npv: 96% with IHC and 94% without: false-negative rate 9.8% / step serial sectioning and IHC provides a higher npv
Ross [19] / 2002 / first international conference on SLNB in HN cancer / 316 pts with HNSCC (pooled multicenter data) / - / - / id-rate: 95%
sens: 90% / similar sens compared with ND;
learning curve;
Murer[20] / 2011 / side effects SLNB vs. ND / 62 pts with T1 or T2 oral and oropharyngeal SCC / 99mTc-nanocolloids / pre-op: LSG(dynamic, static);
intra-op: γ-probe; / SLNB less shoulder impairment and better shoulder function; / SLNB compared with ND has less postoperative morbidity
Schiefke [21] / 2009 / side effects SLNB vs. ND / 49 pts with oral and oropharyngeal SCC (T1-T4) / 99mTc-nanocolloids / pre-op: LSG (dynamic, static);
intra-op: γ-probe / no difference between health-related QOL; disease-specific QOL scores lower in SLNB group; / significantly better functional outcome after SLNB vs.ND;
Hernando[22] / 2014 / side effects SLNB vs. neck dissection / 73 pts with T1 or T2 oral SCC / 99mTc-nanocolloids / one day protocol;
pre-op: LSG (dynamic, static);
intra-op: γ-probe; / - / SLNB significantly less shoulder dysfunction and average scar length
O’Connor [26] / 2013 / cost-effectiveness / 481 pts T1 or T2 oral SCC (SENT trial) / - / - / 25% SLN+, 75% SLN-, 3% false negative SLN;
SLNB 0.35-0.60 the cost of conventional surgery / SLNB appears to be cheaper
Govers [27] / 2013 / cost-effectiveness / T1 or T2 oral SCC, modeling study / - / - / - / SLNB followed by ND or watchful waiting is the most cost-effective strategy
Flach [37] / 2012 / SLNB in previously treated neck / 22 pts with oral SCC / - / pre-op: LSG and SPECT/CT;
intra-op: γ-probe and blue dye / id-rate: 100% for contralateral treatment; 83% with ipsi/bilateral treatment;
npv: 100% / SLNB in previous treated neck is feasible
Broglie [25] / 2013 / size of SLN metastasis impact on survival / 111 pts with T1 or T2oropharyngeal SCC / - / pre-op: LSG (dynamic, static); SPECT/CT;
intra-op: γ-probe; / significant difference in DSS in SLN-. vs. ITCs; OS and DSS different between SLN-and micrometastases; / even small tumor deposits have impact on tumor control and survival
Broglie [41] / 2011 / SLNB long-term experience
(5 year follow up) / 79 pts with oral or oropharyngeal T1/T2; / 99mTc-colloid / preoperative: LSG and SPECT/CT;
intraoperative: γ-probe; / SLN- vs. SLN+:
OS: 80 vs. 74%
DFS: 85 vs 73%
DSS: 87 vs. 77% / neck control rate in SLN- pts is superior to SLN+ ones with shorter DSS
Dequanter [42] / 2013 / SLNB long-term results / 31 pts T1 or T2 oral and oropharyngeal SCC / 99mTc-nanocolloids / pre-op: static LSG;
intraoperative: γ-probe; / sens, spec, npv: 100%
neck control rate: 88% in SLNp+ vs. 100% in SLN-. / SLN- pts had an excellent neck control rate;
Pezier [44] / 2012 / 2-year follow up / 59 pts with T1 or T2 oral SCC / pre-op: LSG;
intra-op: blue dye and γ-probe; / SLN- vs. SLN+
OS: 98% vs. 68%
DSS: 100% vs. 82%
LRFS: 96% vs. 84%
RRFS: 96% vs. 100% / OS and DSS was significantly better in SLN- pts
Stoeckli [52] / 2005 / second international conference / 379 pts HNSCC / - / - / id-rate: 97%
npv: 96% / summarizes technical aspects for successful procedure
Flach [54] / 2014 / defining SLNs on LSG / 16 observers defined SLN in 9 patients / 99mTc-nancolloid / pre-op: LSG (dynamic, planar) with/without SPECT/CT / interobserver variability with fair agreement / moderate agreement defining SLNs was shown
Melkane [58] / 2012 / 10 year experience / 166 pts with T1 or T2 oral SCC / 99mTc rhenium sulfur / pre-op: dynamic LSG;
intra-op: γ-probe; / npv: 95%
SLN involvement correlated with tumor location, stage, depth of invasion and lymphovascular involvement; / micrometastases have clinical significance;
SLNB excellent staging method
Den Toom [62] / 2014 / VU University experience: follow up / 90 pts T1 or T2 oral SCC / 99mTc-nancolloid / pre-op: LSG;
intra-op: blue dye andγ-probe; / id-rate: 99%
sens: 93%; npv: 97%;
OS: 100 vs. 73%
DFS: 84 vs. 88% / confirmed upstaging of SLNB procedure;
OS reduced in SLN+
Flach[63] / 2014 / Dutch multicenter trial: follow up / 62 pts with T1 or T2 oral SCC / 99mTc-nancolloid / pre-op: LSG (dynamic, static);
intra-op: γ-probe; / neck control rate: 97 vs. 95% in SLN+
sens: 80%; NPV: 88%;
DSS: 97 vs. 85% (sign). / SLNB reduces the risk of occult metastases from 40% to 8%
Gurney [64] / 2012 / implication of SLN+ (multicenter) / 109 pts with T1 or T2 oral SCC / - / - / additional positive nodes in 34%; LN+ outside the SLN basin impact outcome / number and position of LN+ may identify different prognostic groups
Marcinow [70] / 2013 / 99mTc-tilmanocept / 20 pts with T1 or T2 oral cancer / 99mTc-tilmanocept / pre-op: LSG and SPECT/CT;
intra-op: γ-probe; / npv: 100%
SPECT/CT identified additional nodes in 55% of cases / high npv and low false-negative rate, promising agent also for FOM
Agrawal [71] / 2015 / 99mTc-tilmanocept / 101 pts with T1-T4 HNSCC (79 intraoral) / 99mTc-tilmanocept / one day or two day;
pre-op: LSG ± dynamic and SPECT/CT
intra-op: γ-probe; / id-rate: 97%
npv: 95%;
acc: 99%;
no difference between one or two day protocol / high rate for SLN identification, high npv and overall accuracy
Heuveling [72] / 2012 / value of late static LSG / 60 pts with T1 or T2 oral SCC / 99mTc-nancolloid / pre-op: dynamic and static imaging early and late (2-4 h);
intra-op: blue dye and γ-probe; / 27% with SLN in early images additional SLNs in late;
9 pts only in late images SLNs identification / additional late imaging only in selected cases to be performed
Mizokami [84] / 2013 / superparamagnetic iron oxid- based SLN mapping / 3 pts with tongue tumor / magnetic particlesvs. 99mTc-colloid / magnetic resonance imaging compared with 99mTc-based LSG / particles were incorporated in all SLNs; after 10 min SLNs could be visualized / feasible, further studies necessary
Heuveling[86] / 2013 / 89Zr-nanocolloid albumin / 5 pts with oral cancer / 89Zr-nanocolloid albumin;
99mTc-nancolloid / PET/CT LSG vs. conventional LSG and SPECT/CT / identical drainage patterns; PET/CT identified near-the- injection-site SLNs / feasibility shown
Vermeeren [92] / 2010 / intraoperative imaging / 25 pts with oral SCC (10 pts) or HN melanoma (15 pts) / 99mTc-nancolloid / pre-op: LSG and SPECT/CT;
intra-op: portable γ-camera and γ-probe; / SLNs at difficult sites were localized more efficiently; 9 additional nodes with gamma camera / feasibility shown; lead to detection of more SLNs
Mandapathil [100] / 2013 / fhSPECT / 5 pts with HN SCC / 99mTc-nancolloid / intra-op tracer injection;
intra-op: fhSPECT / 9 SLNs were detected; 3 pts SLN+, but no further positive LNs in ND / feasibility shown
Bluemel [101] / 2014 / fhSPECT / 23 pts with oral SCC, T1 or T2 / 99mTc-nancolloid / pre-op: LSG (dynamic, static) and SPECT/CT;
intra-op: fhSPECT / id-rate: 98%
acc for final N-stage compared with ND: 100% / also FOM tumors high SLN identification rate
Heuveling [103] / 2014 / fhSPECT / 66 pts with oral SCC / 99mTc-nancolloid / pre-op: dynamic LSG and SPECT/CT;
intra-op: fhSPECT / detection rate: 94%
in 24% detection of SLN was facilitated / fhSPECT facilitating SLN detection; not all near-the-injection-site SLNs were found
Sebbesen [65] / 2014 / 3 follow-up of SLN- pts / 53 pts with T1 or T2 oral SCC / - / preoperative: dynamic and planar LSG;
SPECT/CT / no case of isolated N-recurrence / false negative rate of 0%
van der Berg [106] / 2012 / indocyanine green (ICG)-99mTc-nanocolloid
= hybrid tracer / 14 pts with oral SCC / indocyanine green (ICG)-99mTc-nanocolloid / pre-op: LSG and SPECT/CT;
intra-op: γ-probe and near-infrared fluorescence camera / in 4 pts near-the-injection-site SLNs were identified by fluorescence / feasibility,
value in SLNs next to the injection site
van der Vorst [107] / 2013 / indocyanine green (ICG) adsorbed to human serum albumin / 10 pts with oral SCC / ICG :HSA / Mini-FLARE imageguided surgery system / detection rate: 1 or more SLNs in each pt; / feasibility shown, but quickly tracer migration
Borbon-Arce [108] / 2014 / indocyanine green (ICG)-99mTc-nanocolloid
= hybrid tracer / 26 pts with HN malignancies (9 oral SCC, 16 melanomas) / indocyanine green (ICG)-99mTc-nanocolloid / pre-op: LSG and SPECT/CT;
intra-op: gamma camera, γ-probe and near-infrared fluorescence camera / SLN identification in 98% of pts using multimodality approach; / 26% additional SLNs using multimodality approach
Daisne [110] / 2014 / SPECT/CT SLN-guided superselective prophylactic irradiation / 10 pts with HN SCC eligible for radiotherapy / 99mTc-nancolloid / dynamic LSG and SPECT/CT / 2.9 nodes per pts were detected; in all but one identical to conventionally determined RT field / feasible, phase II studies necessary

Tc: Technetium; US: ultrasound; FNAC: fine-needle aspiration cytology; SLNB: sentinel lymph node biopsy; pts: patients; SCC: squamous cell carcinoma;pre-op: preoperative; intra-op: intraoperative; vs.: versus; LSG: lymphoscintigraphy; sens: sensitivity; spec: specificity; ppv: positive predictive value; npv: negative predictive value;acc: accuracy; id-rate: identification/ detection rate; FOM: floor of the mouth; HN: head and neck; QOL: quality of life; IHC: immunohistochemistry; ND: neck dissection; SLN+: tumor-positive lymph nodes; SLN-: tumor-negative lymph nodes; SENT: sentinel European node trial; DSS: disease-specific survival; OS: overall survival; DFS: disease-free survival; LRFS: local recurrence-free survival; RRFS: regional recurrence-free survival; RT: radiotherapy;

*the studies reporting on the relevance of SPECT/CT were already summarized by Wagner et al. [75];

#without letters, case reports and meta-analysis