- Email: [email protected]
Sentinel lymph node biopsy in malignant melanoma of the head and neck
Accepted Manuscript Sentinel lymph node biopsy in malignant melanoma of the head and neck Roman Kia Rahimi-Nedjat, MD DMD, Bilal Al-Nawas, MD DMD PhD, Andrea Tuettenberg, MD PhD, Keyvan Sagheb, MD DMD, Stephan Grabbe, MD PhD, Christian Walter, MD DMD PhD PII:
S1010-5182(18)30111-2
DOI:
10.1016/j.jcms.2018.04.011
Reference:
YJCMS 2953
To appear in:
Journal of Cranio-Maxillo-Facial Surgery
Received Date: 22 January 2018 Revised Date:
15 March 2018
Accepted Date: 4 April 2018
Please cite this article as: Rahimi-Nedjat RK, Al-Nawas B, Tuettenberg A, Sagheb K, Grabbe S, Walter C, Sentinel lymph node biopsy in malignant melanoma of the head and neck, Journal of CranioMaxillofacial Surgery (2018), doi: 10.1016/j.jcms.2018.04.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Sentinel lymph node biopsy in malignant melanoma of the head and neck
Roman Kia Rahimi-Nedjat MD DMDa, Bilal Al-Nawas MD DMD PhDa, Andrea
Christian Walter MD DMD PhDa a
Stephan Grabbe MD PhDb,
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Tuettenberg MD PhDb, Keyvan Sagheb MD DMDa,
Department of Oral and Maxillofacial Surgery of the University Medical Center of the
Department of Dermatology of the Johannes Gutenberg-University, Langenbeckstr. 1,
55131 Mainz, Germany
Correspondence:
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Roman Kia Rahimi-Nedjat, MD DMD
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b
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Johannes Gutenberg-University, Augustusplatz 2, 55131 Mainz, Germany
Department of Oral and Maxillofacial Surgery, University Medical Center of the
Augustusplatz 2
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55131 Mainz
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Johannes Gutenberg-University
Germany
Telephone:
0049 (0) 6131-173761
Fax:
0049 (0) 6131-178468
Email:
[email protected]
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Introduction With 200,000 new cases per year, malignant melanoma is one of the most common solid tumors among men and women, and yet the incidence is still increasing with an
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annual growth rate of 6% for the male population in Germany (Erdmann et al. 2013, Krebsgesellschaft 2016).
Due to intensified preventive care for skin cancers over recent years, an increasing
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proportion of the newly diagnosed melanomas are shallow tumors (less than 1 mm thick). The life expectancy of these patients shows almost no difference in comparison
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with the general population. However, with increasing tumor thickness, the overall survival rate decreases rapidly (Manola et al. 2000, Eisemann et al. 2012, Kaatsch 2012, Ferlay et al. 2013, Krebsgesellschaft 2016).
The occurrence of regional metastases at the time of diagnosis is considered to be one
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of the most important prognostic factors. Whilst elective lymph node dissection (ELND) was traditionally performed as a routine diagnostic and operative procedure in the treatment of malignant melanoma, sentinel lymph node biopsy (SLNB) is nowadays
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commonly accepted as the gold standard. Introduced by Morton in the early 1990s, this method is based on the assumption that the lymphatic flow follows a constant
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physiological and anatomical pattern, with one lymph node receiving direct drainage from the tumor site (Morton et al. 1992, de Bree and Nieweg 2015). Several studies have described SLNB as a highly accurate method, with lower complication rates than ELND, especially in patients with intermediate-thickness tumors of 1 mm to 4 mm, for which metastases occur only in 20% of cases (Morton et al. 1992, Morton et al. 2006, Madu et al. 2017) However, studies are increasingly showing quite a
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high rate of false-negative findings in SLNB, which can lead to worse overall survival in these patients (Sim et al. 1978, Caraco et al. 2007, Madu et al. 2017). Due to the complexity of the lymphatic structures in the head and neck region, the aim
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of this study was to analyze SLNB in the specific subpopulation of head and neck melanoma patients, investigating the localization of the SLN according to the localization of the primary tumor. The number of false-negative findings in SLNB and its
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benefits over radiological staging were further subjects of this study.
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Materials and Methods In a retrospective study, data for patients who underwent surgical treatment due to a
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malignant melanoma of the head and neck region in the Department of Oral and Maxillofacial Surgery at the Johannes Gutenberg-University of Mainz Medical Center between 2010 and 2016 were evaluated. Epidemiological and treatment data were extracted from electronic health records.
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Using surgery and histopathological reports, the lymph nodes were identified as either
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SLN or non-SLN if further lymph nodes were extirpated. The correct number of resected lymph nodes and their precise localization were recorded. A false-negative SLN was defined as a lymphatic metastasis found in the exact same region as the previously resected SLN within the follow-up period.
In addition, reports from preoperative radiological assessments such as computer
findings.
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tomography, MRI, and ultrasound were screened and compared with the histological
Data evaluation was then performed using the Χ2 test and exact Fisher test for
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categorial variables, and the t-test and Mann-Whitney U-test for continuous variables.
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Results 93 patients with an average age of 63.1 years (± 17.1 years; 74.2% ♂, 25.8% ♀) were treated during the observed period.
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The most frequent localizations of the melanomas were the cheek (20.4%) and the ears (20.4%), followed by the hair-bearing region (15.1%). Superficial spreading and nodular malignant melanoma were diagnosed most often (both 25.8%), followed by lentigo
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maligna melanoma (21.5%). The median tumor thickness was 1.9 mm (± 2.2 mm). Most patients were diagnosed with a T2-melanoma (36.6%), followed by 23.7% with a T4-
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melanoma.
Of these 93 patients four patients received a primary complete neck dissection due to cervical metastasis observed during preoperative staging. A further 15 patients either rejected the SLNB or received systemic therapy due to distant metastases at primary
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diagnosis. Overall, 79.6% (n = 74) underwent SLNB.
All patients who underwent SLNB were operated on by specialists or senior consultants from our department. The sentinel marking was performed by the department of nuclear
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medicine using an injection of Technetium99 in the primary tumor the day before surgery. An ink cross showed the region of the identified SLN and prior to surgery the
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location of the SLN was additionally controlled by ultrasound. Intraoperative identification of the SLN was then performed with a gamma probe.
SLN overview
A mean of two lymph nodes per patient were extirpated (range, 1–16). However, not every one of those was an SLN because other, directly adjacent, nodes were often
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removed intraoperatively as well. Out of a total of 256 removed lymph nodes, 154 were actual SLNs, with a mean number of 2 SLNs removed per patient (range 1–7). 18.9% (n = 14) of the patients had a positive SLN. There was no significant correlation
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between the number of surgically removed lymph nodes (p = 0.114) or SLNs (p = 0.113) and the occurrence of metastases. Most of the metastases were found in patients with
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T3 and T4 melanomas (Table 1).
Localization of the sentinel
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Most of the SLNs in this study were found in the upper cervical regions IIa (20.8%) and IIb (17.5%), according to Robbins. The third most common site of SLNs was around the parotid gland (16.9% of cases). Altogether, 39 SLNs were found in the lymph node regions that are typically not part of a neck dissection (parotidal, retroauricular, occipital,
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and Level VI), accounting for 25.3% of all removed SLNs.
It was not possible to find a standard pattern in the drainage site because the primary tumor localizations were associated with a wide range of SLN regions. For example,
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melanoma located on the ear drained into ten different regions, while melanoma of the
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hair-bearing region drained into nine (Figure 1 and Table 2).
Comparison of preoperative staging and histology In order to check the precision of the preoperative imaging, the radiological reports for all 154 SLNs were compared with the histological findings. 88.3% of the SLNs were preoperatively assessed as benign, while 11.7% showed suspicious changes either in size, configuration, or internal structure.
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Of 154 SLNs, 12.3% (n = 19) showed a metastasis, which in 11 of the cases (7.1% of all SLNs) was microscopic and in eight (5.2% of all SLN) was macroscopic. While all of the SLNs with a macroscopic metastasis were reported as being suspicious in the
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preoperative staging, only four of the SLNs with a microscopic metastasis were diagnosed correctly. This means that 36.8% of the metastatic SLNs were not identified as such using standard imaging techniques as CT-scan, MRI, or ultrasound, and while
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the sensitivity of these procedures for macroscopic metastases is 1.0, preoperative staging shows a poor sensitivity of 0.36 for microscopic metastases. Accordingly,
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overall sensitivity is 0.63 and specificity 0.96.
False-negative SLNs
Follow-up data were found for 70 out of 74 patients, with 24.3% (n = 17) of these
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showing at least one further event, most of which (17.1%; n = 12) were cervical metastases, followed by pulmonary metastases (4.3%; n = 3). The median duration until a further event occurred was 9 months (range 3–77). However, cervical masses
the initial surgery.
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occurred considerably earlier as all of them were diagnosed during the first year after
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Of the 17 patients, only four were positive according to the initial SLNB. Three of these showed a cervical recurrence while one had a pulmonary metastasis. The patients with an initially negative SLN showed another cervical mass in 15.5% (n = 9) of cases. In seven cases, the new relapse (12.0% of the initially negative SLNs; 10% of all patients with follow-up data) was located in the same region as the initially removed SLN (Table 3). Madu et al. found a false-negative rate of 26.9% (Madu et al. 2017). 6
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Discussion The aim of this study was a retrospective overview of SLNB of head and neck melanoma patients. Altogether, 93 patients were included, of which only 74 received an
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SLNB; 154 SLNs were removed.
As described before, SLNB has commonly replaced ELND in the initial treatment of malignant melanoma. Complete lymph node dissection as a diagnostic intervention has
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become obsolete because metastases occur in only 20% of all cases, which means that 80% of the patients might be overtreated. This is of particular importance because
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ELND can result in higher morbidity. More importantly, cervical ELND is a procedure that was historically adapted from the treatment of oropharyngeal tumors, and therefore only nodal regions important for oropharyngeal cancer are removed as standard. Even though different modifications of the outdated radical neck dissection have been
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described to date, most of them lack the inclusion of cervical regions alongside the Robbins levels (Balch et al. 1979, Robbins et al. 1991, Robbins et al. 2002, Werner 2002).
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The relevance of these regions is indeed underlined by the data in our study. Although 42.9% of all SLNs could be found in the upper cervical lymph node regions Ia to IIb,
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more than one quarter of SLNs were not situated in one of the classically removed regions, but were rather located around the parotid gland, retroauricular region, occipital region, or in Level VI according to Robbins. Furthermore, it was not possible to find a constant pattern in the lymphatic drainage because we noted several different SLN localizations for each tumor site regardless of its anatomic size. The reason lies in the complexity of the cervical lymphatic system, which is why small changes between two localizations can lead to significant variations in drainage directions. Moreover, two 7
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tumors of the exact same localization can have SLNs in different regions because the lymph in the head and neck region can drain in different directions (Werner 1995, Werner 2002, Ferlito et al. 2006, Werner 2007, de Bree and Nieweg 2015, Eisenmenger
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and Wiggins 2015).
While SLNB is thought to be less invasive than ELND, it does not have a therapeutic effect because it is only meant to be a diagnostic tool in melanoma treatment (Morton et
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al. 2014, Madu et al. 2017). Considering that powerful diagnostic tools such as ultrasound and high-resolution imaging techniques like CT or MRI exist, the benefit of a
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surgical procedure done purely for diagnostic reasons is questionable. In our study, the preoperative reports for all 154 SLNs were reviewed and compared with the histological findings. Positive results showing either microscopic or macroscopic metastases were found in 18.5% of our patients, which is concordant with other studies (Balch et al.
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1981, McMasters et al. 2001, Berk et al. 2005, Chen et al. 2016, Fortes et al. 2016, Faut et al. 2017). 11.7% of all SLNB patients showed suspicious lymph nodes in the preoperative staging, of which two thirds were confirmed as metastases. All patients
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with macroscopic metastases were diagnosed correctly in advance. On the other hand, however, 9.5% of all patients were not diagnosed correctly, because only four out of 11
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microscopic metastases showed suspicious changes in the lymph node configuration, which means that 63.6% of these patients were not diagnosed correctly. In fact, several authors have described that microscopic filiae evade diagnostic imaging, which is why therapeutic decisions should not be based only on radiologic imaging (van den Brekel et al. 1996, Tardelli et al. 2016). The benefit of SLNB over radiological imaging therefore seems obvious. This has also been proven by Morton et al. in a prospective trial that
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compared SLNB with nodal observation. SLNB showed a significant improvement in disease-free survival as well as melanoma-specific survival (Morton et al. 2014). Yet SLNB seems to be an error-prone procedure. While initial studies reported false-
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negative rates of less than 1%, increasingly publications have stated that false-negative findings can be found in up to 20% of the patients (Morton et al. 1992, Morton et al. 2006, Caraco et al. 2007). Although there is no conformity in the definition of the false-
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negative rate, an increasing number of authors claim that it should be calculated as the negative predictive value. This number was as high as 26.9% in our collective, and
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accordingly higher than the rate found in other studies. The reasons for false-negative SLNBs have been described extensively by different authors, and it is clear that almost every aspect of SLNB, including its definition, preoperative marking, intraoperative identification, the number of excised lymph nodes, and their histopathological
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assessment, can lead to the examination of non-SLNs instead of the actual SLNs (Nieweg et al. 2001, Nieweg and Estourgie 2004, Manca et al. 2014a, Manca et al. 2014b) The high number in our study, however, is most likely related to the specific
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anatomical region because most of the studies include SLNs from every lymphatic system, while we only investigated cervical SLNB. The cervical lymphatic region is
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known to be the most complex one, with more than 300 lymph nodes, multilaterally directed lymphatic vessels, closely localized lymph nodes, and mostly only small SLNs (Werner 2002, Uren 2004, Werner et al. 2004, Werner 2007). The extirpation of the correct SLN, however, is crucial for melanoma patients because those with falsenegative SLNs have shown a significantly worse overall survival compared with patients with an initially positive SLN (Caraco et al. 2007, Morton et al. 2014). While some studies suggest removing more than just the marked SLN to improve the diagnostic 9
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safety, our data could not show a significant relation between the number of extirpated lymph nodes or SLNs and subsequent metastases. Nevertheless, the benefits of SLNB outweigh its costs. Compared with ELND, SLNB is a
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smaller surgical intervention, which shows less morbidity; its even bigger advantage lies in the individually adjusted lymph node extirpation, especially in the cervical region. According to the guidelines, CLND is nowadays only required when a positive SLN can
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be found or in cases of clinically obvious metastases at the time of diagnosis. However, this indication for CLND is critically discussed because recent studies have not been
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able to find a benefit of CLND over no dissection in patients with a positive SLN (Leiter et al. 2016).
The occurrence of lymphatic filiae remains one of the most important prognostic factors in the treatment of malignant melanoma, so a thorough diagnosis is absolutely
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essential. Although SLNB goes beyond radiological assessments, there still remains a diagnostic gap due to its high rate of false-negative SLNs, which means that all patients should be followed up closely.
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The limitation of this study is its retrospective design because data could only be collected from electronic records. Our data suggest that more investigations should be
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conducted on SLNB, with a focus on head and neck malignant melanoma.
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Conclusion Our study shows that SLNB is especially appropriate for the diagnosis of microscopic metastases in melanoma, because these lymph nodes generally evade conventional
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radiologic imaging and ultrasound. The low sensitivity of the imaging techniques is of particular relevance because microscopic metastases are one of the most important prognostic factors in early-stage melanoma patients. However, our study also shows
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that SLNB in the head and neck region, with its complex lymphatic system, has a high
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short-term follow up after SLNB.
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risk of false-negative SLNs, which is why we recommend that patients should remain in
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Acknowledgements and conflict of interest statement There has been no work on human subjects in this study. Declarations of interest: none
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The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
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Roles of the authors: RK Rahimi-Nedjat
K Sagheb
S Grabbe
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C Walter
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A Tuettenberg
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B Al-Nawas
Conception and design of the study Acquisition of data Interpretation of data Drafting of the article Interpretation of data Revising of the manuscript Final approval of the manuscript Interpretation of data Revising of the manuscript Final approval of the manuscript Interpretation of data Revising of the manuscript Final approval of the manuscript Interpretation of data Revising of the manuscript Final approval of the manuscript Interpretation of data Revising of the manuscript Final approval of the manuscript
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Werner, J. A.: Patterns of metastasis in head and neck cancer. Cancer Treat Res 135:203–207, 2007 Werner, J. A., A. A. Dunne, B. J. Folz, R. Moll and T. Behr: Value of sentinel lymphadenectomy in head and neck cancer. Ann Surg Oncol 11:267S–270S, 2004
Captions to illustrations
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Figure 1 Distribution of SLNs according to primary tumor localizations
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Table 1: Overview of the total number of extirpated lymph nodes and the proportion of actual SLNs (positive/negative)
SLNs Positive
Negative
0 (0%)
23 (100%)
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T classification T1
Number of extirpated lymph Actual SLNs nodes 36 23 (63.9%) 107
62 (59.6%)
6 (9.7%)
56 (90.3%)
T3
70
33 (47.1%)
8 (24.2%)
25 (75.8%)
T4
30
26 (86.6%)
3 (11.5%)
23 (88.5%)
Tx
13
10 (76.9%)
2 (20.0%)
8 (80.0%)
Total
256
154 (62.9%)
19 (12.3%)
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T2
135 (87.7%)
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Table 2: Overview of the frequency and localization of SLNs in comparison with primary tumor localizations. Regions Ia-VI are
Ia
Ib
IIa
IIb
III
IV
V
Scalp
5
7
4
1
2
Neck
4
2
2
4
4
Occiput
1
2
Nuchal 2
2
1
2
1
Upper lid 5
6
3
Temple
3
2
1
Forehead
1
3
Lower lid Cheek
1 1
2
Lip/chin Total
10 1
2
5
32
2
1
2
3
Parotid Retroauri
Nuchal
al
2
1
3
2
1
1
nodes
3
27
55
1
17
27
11
21
5
16
1
7
17
1
1
1
33
51
4
13
13
1
6
6
1
1
8
1
lymph SLNs
1
cular
2
1
2
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1
EP
1
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Ear
pital
4
2
Nose
VI
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localization
All
Region Region Region Region Region Region Region Region Subocci
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Tumor
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according to Robbins et al.
3
2
1
5
26
41
1
7
7
154
256
1
2
1
1
27
18
14
17
2
2
4
26
5
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Table3: Comparison of preoperative reports and histological findings for SLNs
Preoperative
Preoperative
benign
suspect
129 (94.9%)
6 (33.3%)
135 (87.6%)
Microscopic metastases
7 (5.1%)
4 (22.2%)
11 (7.1%)
Macroscopic metastases
0 (0.0%)
8 (44.4%)
8 (5.2%)
136 (88,3%)
18 (11.7%)
154 (100%)
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SC
Total
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Negative SLNs
Total
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35
30 lip/chin
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cheek
25
lower lid forehead
20
temple ear
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15
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10
5
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0
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Fig. 1: Distribution of SLN according to the primary tumor localizations
upper lid nose nuchal occiput neck scalp
S1010-5182(18)30111-2
DOI:
10.1016/j.jcms.2018.04.011
Reference:
YJCMS 2953
To appear in:
Journal of Cranio-Maxillo-Facial Surgery
Received Date: 22 January 2018 Revised Date:
15 March 2018
Accepted Date: 4 April 2018
Please cite this article as: Rahimi-Nedjat RK, Al-Nawas B, Tuettenberg A, Sagheb K, Grabbe S, Walter C, Sentinel lymph node biopsy in malignant melanoma of the head and neck, Journal of CranioMaxillofacial Surgery (2018), doi: 10.1016/j.jcms.2018.04.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Sentinel lymph node biopsy in malignant melanoma of the head and neck
Roman Kia Rahimi-Nedjat MD DMDa, Bilal Al-Nawas MD DMD PhDa, Andrea
Christian Walter MD DMD PhDa a
Stephan Grabbe MD PhDb,
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Tuettenberg MD PhDb, Keyvan Sagheb MD DMDa,
Department of Oral and Maxillofacial Surgery of the University Medical Center of the
Department of Dermatology of the Johannes Gutenberg-University, Langenbeckstr. 1,
55131 Mainz, Germany
Correspondence:
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Roman Kia Rahimi-Nedjat, MD DMD
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b
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Johannes Gutenberg-University, Augustusplatz 2, 55131 Mainz, Germany
Department of Oral and Maxillofacial Surgery, University Medical Center of the
Augustusplatz 2
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55131 Mainz
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Johannes Gutenberg-University
Germany
Telephone:
0049 (0) 6131-173761
Fax:
0049 (0) 6131-178468
Email:
[email protected]
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Introduction With 200,000 new cases per year, malignant melanoma is one of the most common solid tumors among men and women, and yet the incidence is still increasing with an
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annual growth rate of 6% for the male population in Germany (Erdmann et al. 2013, Krebsgesellschaft 2016).
Due to intensified preventive care for skin cancers over recent years, an increasing
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proportion of the newly diagnosed melanomas are shallow tumors (less than 1 mm thick). The life expectancy of these patients shows almost no difference in comparison
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with the general population. However, with increasing tumor thickness, the overall survival rate decreases rapidly (Manola et al. 2000, Eisemann et al. 2012, Kaatsch 2012, Ferlay et al. 2013, Krebsgesellschaft 2016).
The occurrence of regional metastases at the time of diagnosis is considered to be one
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of the most important prognostic factors. Whilst elective lymph node dissection (ELND) was traditionally performed as a routine diagnostic and operative procedure in the treatment of malignant melanoma, sentinel lymph node biopsy (SLNB) is nowadays
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commonly accepted as the gold standard. Introduced by Morton in the early 1990s, this method is based on the assumption that the lymphatic flow follows a constant
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physiological and anatomical pattern, with one lymph node receiving direct drainage from the tumor site (Morton et al. 1992, de Bree and Nieweg 2015). Several studies have described SLNB as a highly accurate method, with lower complication rates than ELND, especially in patients with intermediate-thickness tumors of 1 mm to 4 mm, for which metastases occur only in 20% of cases (Morton et al. 1992, Morton et al. 2006, Madu et al. 2017) However, studies are increasingly showing quite a
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high rate of false-negative findings in SLNB, which can lead to worse overall survival in these patients (Sim et al. 1978, Caraco et al. 2007, Madu et al. 2017). Due to the complexity of the lymphatic structures in the head and neck region, the aim
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of this study was to analyze SLNB in the specific subpopulation of head and neck melanoma patients, investigating the localization of the SLN according to the localization of the primary tumor. The number of false-negative findings in SLNB and its
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benefits over radiological staging were further subjects of this study.
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Materials and Methods In a retrospective study, data for patients who underwent surgical treatment due to a
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malignant melanoma of the head and neck region in the Department of Oral and Maxillofacial Surgery at the Johannes Gutenberg-University of Mainz Medical Center between 2010 and 2016 were evaluated. Epidemiological and treatment data were extracted from electronic health records.
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Using surgery and histopathological reports, the lymph nodes were identified as either
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SLN or non-SLN if further lymph nodes were extirpated. The correct number of resected lymph nodes and their precise localization were recorded. A false-negative SLN was defined as a lymphatic metastasis found in the exact same region as the previously resected SLN within the follow-up period.
In addition, reports from preoperative radiological assessments such as computer
findings.
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tomography, MRI, and ultrasound were screened and compared with the histological
Data evaluation was then performed using the Χ2 test and exact Fisher test for
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categorial variables, and the t-test and Mann-Whitney U-test for continuous variables.
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Results 93 patients with an average age of 63.1 years (± 17.1 years; 74.2% ♂, 25.8% ♀) were treated during the observed period.
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The most frequent localizations of the melanomas were the cheek (20.4%) and the ears (20.4%), followed by the hair-bearing region (15.1%). Superficial spreading and nodular malignant melanoma were diagnosed most often (both 25.8%), followed by lentigo
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maligna melanoma (21.5%). The median tumor thickness was 1.9 mm (± 2.2 mm). Most patients were diagnosed with a T2-melanoma (36.6%), followed by 23.7% with a T4-
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melanoma.
Of these 93 patients four patients received a primary complete neck dissection due to cervical metastasis observed during preoperative staging. A further 15 patients either rejected the SLNB or received systemic therapy due to distant metastases at primary
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diagnosis. Overall, 79.6% (n = 74) underwent SLNB.
All patients who underwent SLNB were operated on by specialists or senior consultants from our department. The sentinel marking was performed by the department of nuclear
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medicine using an injection of Technetium99 in the primary tumor the day before surgery. An ink cross showed the region of the identified SLN and prior to surgery the
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location of the SLN was additionally controlled by ultrasound. Intraoperative identification of the SLN was then performed with a gamma probe.
SLN overview
A mean of two lymph nodes per patient were extirpated (range, 1–16). However, not every one of those was an SLN because other, directly adjacent, nodes were often
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removed intraoperatively as well. Out of a total of 256 removed lymph nodes, 154 were actual SLNs, with a mean number of 2 SLNs removed per patient (range 1–7). 18.9% (n = 14) of the patients had a positive SLN. There was no significant correlation
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between the number of surgically removed lymph nodes (p = 0.114) or SLNs (p = 0.113) and the occurrence of metastases. Most of the metastases were found in patients with
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T3 and T4 melanomas (Table 1).
Localization of the sentinel
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Most of the SLNs in this study were found in the upper cervical regions IIa (20.8%) and IIb (17.5%), according to Robbins. The third most common site of SLNs was around the parotid gland (16.9% of cases). Altogether, 39 SLNs were found in the lymph node regions that are typically not part of a neck dissection (parotidal, retroauricular, occipital,
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and Level VI), accounting for 25.3% of all removed SLNs.
It was not possible to find a standard pattern in the drainage site because the primary tumor localizations were associated with a wide range of SLN regions. For example,
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melanoma located on the ear drained into ten different regions, while melanoma of the
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hair-bearing region drained into nine (Figure 1 and Table 2).
Comparison of preoperative staging and histology In order to check the precision of the preoperative imaging, the radiological reports for all 154 SLNs were compared with the histological findings. 88.3% of the SLNs were preoperatively assessed as benign, while 11.7% showed suspicious changes either in size, configuration, or internal structure.
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Of 154 SLNs, 12.3% (n = 19) showed a metastasis, which in 11 of the cases (7.1% of all SLNs) was microscopic and in eight (5.2% of all SLN) was macroscopic. While all of the SLNs with a macroscopic metastasis were reported as being suspicious in the
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preoperative staging, only four of the SLNs with a microscopic metastasis were diagnosed correctly. This means that 36.8% of the metastatic SLNs were not identified as such using standard imaging techniques as CT-scan, MRI, or ultrasound, and while
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the sensitivity of these procedures for macroscopic metastases is 1.0, preoperative staging shows a poor sensitivity of 0.36 for microscopic metastases. Accordingly,
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overall sensitivity is 0.63 and specificity 0.96.
False-negative SLNs
Follow-up data were found for 70 out of 74 patients, with 24.3% (n = 17) of these
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showing at least one further event, most of which (17.1%; n = 12) were cervical metastases, followed by pulmonary metastases (4.3%; n = 3). The median duration until a further event occurred was 9 months (range 3–77). However, cervical masses
the initial surgery.
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occurred considerably earlier as all of them were diagnosed during the first year after
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Of the 17 patients, only four were positive according to the initial SLNB. Three of these showed a cervical recurrence while one had a pulmonary metastasis. The patients with an initially negative SLN showed another cervical mass in 15.5% (n = 9) of cases. In seven cases, the new relapse (12.0% of the initially negative SLNs; 10% of all patients with follow-up data) was located in the same region as the initially removed SLN (Table 3). Madu et al. found a false-negative rate of 26.9% (Madu et al. 2017). 6
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Discussion The aim of this study was a retrospective overview of SLNB of head and neck melanoma patients. Altogether, 93 patients were included, of which only 74 received an
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SLNB; 154 SLNs were removed.
As described before, SLNB has commonly replaced ELND in the initial treatment of malignant melanoma. Complete lymph node dissection as a diagnostic intervention has
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become obsolete because metastases occur in only 20% of all cases, which means that 80% of the patients might be overtreated. This is of particular importance because
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ELND can result in higher morbidity. More importantly, cervical ELND is a procedure that was historically adapted from the treatment of oropharyngeal tumors, and therefore only nodal regions important for oropharyngeal cancer are removed as standard. Even though different modifications of the outdated radical neck dissection have been
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described to date, most of them lack the inclusion of cervical regions alongside the Robbins levels (Balch et al. 1979, Robbins et al. 1991, Robbins et al. 2002, Werner 2002).
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The relevance of these regions is indeed underlined by the data in our study. Although 42.9% of all SLNs could be found in the upper cervical lymph node regions Ia to IIb,
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more than one quarter of SLNs were not situated in one of the classically removed regions, but were rather located around the parotid gland, retroauricular region, occipital region, or in Level VI according to Robbins. Furthermore, it was not possible to find a constant pattern in the lymphatic drainage because we noted several different SLN localizations for each tumor site regardless of its anatomic size. The reason lies in the complexity of the cervical lymphatic system, which is why small changes between two localizations can lead to significant variations in drainage directions. Moreover, two 7
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tumors of the exact same localization can have SLNs in different regions because the lymph in the head and neck region can drain in different directions (Werner 1995, Werner 2002, Ferlito et al. 2006, Werner 2007, de Bree and Nieweg 2015, Eisenmenger
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and Wiggins 2015).
While SLNB is thought to be less invasive than ELND, it does not have a therapeutic effect because it is only meant to be a diagnostic tool in melanoma treatment (Morton et
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al. 2014, Madu et al. 2017). Considering that powerful diagnostic tools such as ultrasound and high-resolution imaging techniques like CT or MRI exist, the benefit of a
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surgical procedure done purely for diagnostic reasons is questionable. In our study, the preoperative reports for all 154 SLNs were reviewed and compared with the histological findings. Positive results showing either microscopic or macroscopic metastases were found in 18.5% of our patients, which is concordant with other studies (Balch et al.
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1981, McMasters et al. 2001, Berk et al. 2005, Chen et al. 2016, Fortes et al. 2016, Faut et al. 2017). 11.7% of all SLNB patients showed suspicious lymph nodes in the preoperative staging, of which two thirds were confirmed as metastases. All patients
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with macroscopic metastases were diagnosed correctly in advance. On the other hand, however, 9.5% of all patients were not diagnosed correctly, because only four out of 11
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microscopic metastases showed suspicious changes in the lymph node configuration, which means that 63.6% of these patients were not diagnosed correctly. In fact, several authors have described that microscopic filiae evade diagnostic imaging, which is why therapeutic decisions should not be based only on radiologic imaging (van den Brekel et al. 1996, Tardelli et al. 2016). The benefit of SLNB over radiological imaging therefore seems obvious. This has also been proven by Morton et al. in a prospective trial that
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compared SLNB with nodal observation. SLNB showed a significant improvement in disease-free survival as well as melanoma-specific survival (Morton et al. 2014). Yet SLNB seems to be an error-prone procedure. While initial studies reported false-
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negative rates of less than 1%, increasingly publications have stated that false-negative findings can be found in up to 20% of the patients (Morton et al. 1992, Morton et al. 2006, Caraco et al. 2007). Although there is no conformity in the definition of the false-
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negative rate, an increasing number of authors claim that it should be calculated as the negative predictive value. This number was as high as 26.9% in our collective, and
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accordingly higher than the rate found in other studies. The reasons for false-negative SLNBs have been described extensively by different authors, and it is clear that almost every aspect of SLNB, including its definition, preoperative marking, intraoperative identification, the number of excised lymph nodes, and their histopathological
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assessment, can lead to the examination of non-SLNs instead of the actual SLNs (Nieweg et al. 2001, Nieweg and Estourgie 2004, Manca et al. 2014a, Manca et al. 2014b) The high number in our study, however, is most likely related to the specific
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anatomical region because most of the studies include SLNs from every lymphatic system, while we only investigated cervical SLNB. The cervical lymphatic region is
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known to be the most complex one, with more than 300 lymph nodes, multilaterally directed lymphatic vessels, closely localized lymph nodes, and mostly only small SLNs (Werner 2002, Uren 2004, Werner et al. 2004, Werner 2007). The extirpation of the correct SLN, however, is crucial for melanoma patients because those with falsenegative SLNs have shown a significantly worse overall survival compared with patients with an initially positive SLN (Caraco et al. 2007, Morton et al. 2014). While some studies suggest removing more than just the marked SLN to improve the diagnostic 9
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safety, our data could not show a significant relation between the number of extirpated lymph nodes or SLNs and subsequent metastases. Nevertheless, the benefits of SLNB outweigh its costs. Compared with ELND, SLNB is a
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smaller surgical intervention, which shows less morbidity; its even bigger advantage lies in the individually adjusted lymph node extirpation, especially in the cervical region. According to the guidelines, CLND is nowadays only required when a positive SLN can
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be found or in cases of clinically obvious metastases at the time of diagnosis. However, this indication for CLND is critically discussed because recent studies have not been
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able to find a benefit of CLND over no dissection in patients with a positive SLN (Leiter et al. 2016).
The occurrence of lymphatic filiae remains one of the most important prognostic factors in the treatment of malignant melanoma, so a thorough diagnosis is absolutely
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essential. Although SLNB goes beyond radiological assessments, there still remains a diagnostic gap due to its high rate of false-negative SLNs, which means that all patients should be followed up closely.
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The limitation of this study is its retrospective design because data could only be collected from electronic records. Our data suggest that more investigations should be
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conducted on SLNB, with a focus on head and neck malignant melanoma.
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Conclusion Our study shows that SLNB is especially appropriate for the diagnosis of microscopic metastases in melanoma, because these lymph nodes generally evade conventional
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radiologic imaging and ultrasound. The low sensitivity of the imaging techniques is of particular relevance because microscopic metastases are one of the most important prognostic factors in early-stage melanoma patients. However, our study also shows
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that SLNB in the head and neck region, with its complex lymphatic system, has a high
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short-term follow up after SLNB.
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risk of false-negative SLNs, which is why we recommend that patients should remain in
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Acknowledgements and conflict of interest statement There has been no work on human subjects in this study. Declarations of interest: none
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The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
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Roles of the authors: RK Rahimi-Nedjat
K Sagheb
S Grabbe
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C Walter
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A Tuettenberg
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B Al-Nawas
Conception and design of the study Acquisition of data Interpretation of data Drafting of the article Interpretation of data Revising of the manuscript Final approval of the manuscript Interpretation of data Revising of the manuscript Final approval of the manuscript Interpretation of data Revising of the manuscript Final approval of the manuscript Interpretation of data Revising of the manuscript Final approval of the manuscript Interpretation of data Revising of the manuscript Final approval of the manuscript
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Werner, J. A.: Patterns of metastasis in head and neck cancer. Cancer Treat Res 135:203–207, 2007 Werner, J. A., A. A. Dunne, B. J. Folz, R. Moll and T. Behr: Value of sentinel lymphadenectomy in head and neck cancer. Ann Surg Oncol 11:267S–270S, 2004
Captions to illustrations
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Figure 1 Distribution of SLNs according to primary tumor localizations
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Table 1: Overview of the total number of extirpated lymph nodes and the proportion of actual SLNs (positive/negative)
SLNs Positive
Negative
0 (0%)
23 (100%)
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T classification T1
Number of extirpated lymph Actual SLNs nodes 36 23 (63.9%) 107
62 (59.6%)
6 (9.7%)
56 (90.3%)
T3
70
33 (47.1%)
8 (24.2%)
25 (75.8%)
T4
30
26 (86.6%)
3 (11.5%)
23 (88.5%)
Tx
13
10 (76.9%)
2 (20.0%)
8 (80.0%)
Total
256
154 (62.9%)
19 (12.3%)
AC C
EP
TE D
M AN U
SC
T2
135 (87.7%)
ACCEPTED MANUSCRIPT
Table 2: Overview of the frequency and localization of SLNs in comparison with primary tumor localizations. Regions Ia-VI are
Ia
Ib
IIa
IIb
III
IV
V
Scalp
5
7
4
1
2
Neck
4
2
2
4
4
Occiput
1
2
Nuchal 2
2
1
2
1
Upper lid 5
6
3
Temple
3
2
1
Forehead
1
3
Lower lid Cheek
1 1
2
Lip/chin Total
10 1
2
5
32
2
1
2
3
Parotid Retroauri
Nuchal
al
2
1
3
2
1
1
nodes
3
27
55
1
17
27
11
21
5
16
1
7
17
1
1
1
33
51
4
13
13
1
6
6
1
1
8
1
lymph SLNs
1
cular
2
1
2
TE D
1
EP
1
AC C
Ear
pital
4
2
Nose
VI
M AN U
localization
All
Region Region Region Region Region Region Region Region Subocci
SC
Tumor
RI PT
according to Robbins et al.
3
2
1
5
26
41
1
7
7
154
256
1
2
1
1
27
18
14
17
2
2
4
26
5
ACCEPTED MANUSCRIPT
Table3: Comparison of preoperative reports and histological findings for SLNs
Preoperative
Preoperative
benign
suspect
129 (94.9%)
6 (33.3%)
135 (87.6%)
Microscopic metastases
7 (5.1%)
4 (22.2%)
11 (7.1%)
Macroscopic metastases
0 (0.0%)
8 (44.4%)
8 (5.2%)
136 (88,3%)
18 (11.7%)
154 (100%)
AC C
EP
TE D
M AN U
SC
Total
RI PT
Negative SLNs
Total
ACCEPTED MANUSCRIPT
35
30 lip/chin
RI PT
cheek
25
lower lid forehead
20
temple ear
SC
15
M AN U
10
5
TE D
0
AC C
EP
Fig. 1: Distribution of SLN according to the primary tumor localizations
upper lid nose nuchal occiput neck scalp