^99mTc-Tilmanocept vs. Sulfur Colloid for Sentinel Node Biopsy for Melanoma in the Head and Neck

Abstract

The objective of the study is to compare sentinel lymph node (SLN) identification rates and performance characteristics of lymphoscintigraphy using ^99mTc-sulfur colloid (SC) and ^99mTc-tilmanocept (TL) for head and neck cutaneous melanoma. This study is a retrospective study, conducted at a single, tertiary care cancer center. Patients underwent sentinel lymph node biopsy (SLNB) for head and neck cutaneous melanoma, using SC or TL, between October 2014 and February 2019. Differences in SLN identification rates and performance characteristics between the groups were examined using the Mann–Whitney, or Fisher’s exact test. Sixty patients underwent SLNB, of which 19 employed TL. There were no significant differences between SC vs. TL in operative duration (116 vs. 127 min, P = 0.97), radiation dose (530 vs. 547 μCi, P = 0.27), median number of SLNs removed (3 vs. 2, P = 0.32), or median follow-up (46.3 vs. 38.4 months, P = 0.11). The rates of positive SLNs (17% vs. 37%, P = 0.11), intraoperative non-localization (12% vs. 16%, P = 0.70), and false-negative SLNB (5% each, P = 1.00) were not significantly different between groups. In patients with head and neck melanoma undergoing SLNB, ^99mTc-tilmanocept may not differ from ^99mTc-sulfur colloid in identifying SLNs or other performance characteristics. The added expense related to ^99mTc-tilmanocept and lack of favorable performance data should urge caution in its adoption and promote further examination of its value in similar patient cohorts.

Introduction

Sentinel lymph node biopsy (SLNB) is a valuable tool to detect microscopic occult nodal metastases related to cutaneous melanoma in selected patients with clinically negative regional nodal basins. It provides important prognostic information, helps guide management for patients with cutaneous malignant melanoma, and minimizes risk of complications compared to a neck dissection.

A sentinel lymph node (SLN) is defined as the first node in a nodal basin that receives afferent lymphatic drainage from a relevant primary tumor site [1]. The performance of SLNB for head and neck cutaneous melanoma commonly relies on use of radiopharmaceuticals. The ideal radiotracer should be standardized in preparation, nontoxic, and painless and quickly transported to reside in the first-echelon “sentinel” nodes and retained in those sentinel sites until SLNB is completed. The most commonly used radiopharmaceuticals in the USA are large molecular weight sulfur colloids such as ^99mTc-sulfur colloid (SC), with high SLN identification rates reported in a variety of settings, such as breast surgery where SLN identification rates range between 86 and 99% [2, 3].

However, with wider adoption of SLNB for head and neck cutaneous and mucosal malignancies, several limitations related to use of conventional radiopharmaceuticals have emerged. In a prospective trial involving SLNB for oral cavity cancer, use of SC was associated with a false-negative rate of 5–13%. This was attributed to the lack of specific binding of the molecule [4]. Moreover, traditional radiolabeled colloids have non-standardized preparations with variable molecule size and potential for retention of particles at the injection site resulting in “shine-through” which may interfere with identification of SLNs [5]. The lack of specific binding may narrow the time frame available between radiopharmaceutical injection and SLNB, as the radiotracer may theoretically travel from the first echelon nodes to further downstream nodes.

^99mTc-tilmanocept (TL) is a synthetic radiopharmaceutical product that is designed to improve on the limitations of SC. It consists of multiple diethylenetriaminepentaacetic acid (DTPA) and mannose residues linked to a dextran frame. The ^99mTc is attached to DTPA while the mannose residues bind to mannose receptors (CD206) that are expressed on the surface of reticuloendothelial cells in lymph nodes. TL is a small molecule with a 7.1 nm diameter and a molecular weight 16.7 kDa, which allows for rapid clearance from the injection site, while its specific binding properties enable retention in the first echelon “sentinel” nodes [6].

TL has garnered substantial interest as a radiopharmaceutical for lymphatic mapping in the context of head and neck malignancies including melanoma and oral squamous cell carcinoma. However, the data relating to comparative value of TL over SC in the head and neck for cutaneous melanoma is lacking. With the more recent adoption of TL for lymphatic mapping at our institution, we sought to compare SLN identification rates and assess the performance characteristics of TL versus SC.

Methods

We performed a retrospective study including adult patients (age > 19 years) with a biopsy proven diagnosis of T1–T4 head and neck cutaneous melanoma, clinically negative regional nodal basin, without known distant metastatic disease, who consented to a SLNB between October 1, 2014, and February 30, 2019, at a tertiary cancer center. Patients with melanoma who did not consent to or did not require a SNLB, those without an identifiable primary cutaneous site, and non-melanoma cutaneous malignancies were excluded. Our institution transitioned from SC to TL as the preferred radiopharmaceutical for SLNB in 2018, allowing patient stratification into two cohorts for analyses based on type of radiopharmaceutical used (SC versus TL). The study received Institutional Review Board approval at the Nebraska Methodist Hospital.

Patients discussed their eligibility and suitability for SLNB with their oncology team, and management plans were reviewed at the institutional multidisciplinary treatment planning committee meeting to ensure consensus and adherence to contemporary guidelines. SLNB was performed using the following technique: patients were administered preoperative intradermal, four quadrant, peri-lesional injection of radiopharmaceutical (SC or TL) by a nuclear medicine physician and then underwent dynamic and static planar imaging, as well as single photon emission computed tomography/CT (SPECT). Localization studies were reviewed by the radiology and surgical teams prior to SLNB. The patients then underwent surgery within 30 h of lymphoscintigraphy. Excision of the residual primary tumor, with or without reconstruction, was performed at the time of SLNB. Intraoperatively, SLN localization was facilitated with the use of a gamma probe. Using the 10% rule, the SLNB was considered to be a success if residual activity in the surgical bed was ≤ 10% of the highest reading at the “hotspot.” After removal of all SLNs meeting criteria, the gamma probe was used to examine the nodal basin to ensure that no substantial residual radioactivity remained. All SLNs and non-SLNs were sent for pathological evaluation and were examined after staining with hematoxylin and eosin. Using serial step sections prepared from the cryoblock and paraffin embedded blocks, SLNs were examined using a panel of immunohistochemical staining techniques including S100, MART-1, HMB45, Melan-A, and Sox-10. Apart from the change in choice of radiopharmaceutical agent used for SLNB, the techniques related to radiopharmaceutical injection, radiographic or intraoperative localization, surgical technique of SLN excision, and pathologic assessment of excised nodes were not modified during the course of the study period. Patient with positive sentinel nodes received care including regional lymphadenectomy and adjuvant therapy, if indicated, based on established guidelines.

Baseline patient and tumor characteristics, intraoperative variables, and pathology results were collected through a retrospective review of charts. The primary outcomes of interest included any differences in number of SLNs identified per procedure and the frequency of SLN localization. Secondary outcomes of interest included the following: the frequency of false-negative SLNB, which was defined as development of regional nodal recurrence in a basin that had been previously investigated with SLNB technique, during standard postoperative surveillance; operative duration; radiation dose exposure; and the frequency of positive SLNs in each cohort.

The sample was a convenience sample of eligible patients available during the observational period; there was no a priori completion of a power analysis. Categorical variables are presented as a frequency and percentage whereas continuous variables are presented as median and interquartile range (IQR). After cross-classification by the radiopharmaceutical group, each categorical variable was subsequently examined in an unadjusted manner with the Fisher’s exact test. Continuous variables were cross-classified in a similar manner, and unadjusted differences were examined with the Mann–Whitney test. STATA (version 17.0, StataCorp LLC, College Station, TX, 2021) was used for all analyses, and P < 0.05 indicated statistical significance and all hypothesis tests were two-sided.

Results

Sixty patients met the inclusion criteria, of which 41 patients underwent SLNB with the use of SC and 19 others received TL. The patient demographics and baseline characteristics are summarized in Table 1. There was no statistical evidence of a difference in patient age, sex, T-classification, primary site of melanoma within head and neck, frequency of ulceration, and Breslow depth (all P > 0.05). The median follow-up time was 46.3 months in the SC group (IQR: 27.8 to 70.8 months) versus 38.4 months (IQR: 24.6 to 44.7 months) for the TL group (P = 0.11).

Table 1.

Patient demographics

Clinical characteristic	99mTc-sulfur colloid	99mTc-tilmanocept	P
Sample size,$n$	41	19
Age, years, median (IQR)	69 (54–77)	72 (55–77)	0.39
Male, $n$ (%)	28 (68)	11 (58)	0.56
AJCC T-classification, $n$ (%)			0.11
1a	1 (2)	1 (5)
1b	6 (15)	0 (0)
2a	18 (44)	6 (32)
2b	3 (7)	2 (11)
3a	4 (10)	7 (37)
3b	1 (2)	1 (5)
4a	2 (5)	1 (5)
4b	6 (15)	1 (5)
Primary site, $n$ (%)			0.42
Cheek	8 (20)	7 (37)
Ear	8 (20)	4 (21)
Forehead	4 (10)	0 (0)
Neck	4 (10)	1 (5)
Nose	5 (12)	1 (5)
Scalp	8 (20)	6 (32)
Temple	4 (10)	0 (0)
Ulceration, $n$ (%)	10 (25)	4 (21)	1.00
Breslow depth, mm (IQR)	1.4 (1.1–2.7)	2.0 (1.3–2.8)	0.20
Median follow-up, months (IQR)	46.3 (27.8–70.8)	38.4 (24.6–44.7)	0.11

AJCC American Joint Committee on Cancer, IQR interquartile range

Performance characteristics of the lymphoscintigraphy in each cohort are summarized in Table 2. The frequency of intraoperative SLN identification was not significantly different between the groups (SC versus TL, 36 (88%) vs. 16 (84%)) (P = 0.70). The groups were similar in the number of sentinel nodes excised (3 (1 to 5) vs. 2 (1 to 4)) (P = 0.32). When comparing SC and TL groups, there were no significant differences in the median operative duration (116 (90 to 166) vs. 127 (96 to 150) min), radiation exposure (530 (500 to 550) vs. 547 (510 to 559) μCi), number of hotspots per basin (1.5 (1 to 2) vs. 1 (0 to 2)), and frequency of SLNs found to be positive on pathology (7 (17%) vs. 7 (37%)) (all P > 0.05).

Table 2.

Performance characteristics of lymphoscintigraphy

Clinical outcomes	99mTc-sulfur colloid	99mTc-tilmanocept	P
Operative duration, minutes, median (IQR)	116 (90–166)	127 (96–150)	0.97
Radiation dose, μCi, median (IQR)	530 (500–550)	547 (510–559)	0.27
Number of hotspots, median (IQR)	2 (1–3)	2 (0–2)	0.18
Number of basins, n (%)			0.69
0	6 (15)	4 (21)
1	25 (61)	10 (53)
2	8 (20)	5 (26)
3	2 (5)	0 (0)
Number of sentinel nodes removed, median (IQR)	3 (1–5)	2 (1–4)	0.32
SLN intraoperative identification, $n$ (%)	36 (88)	16 (84)	0.70
Patients with positive SLNB, $n$ (%)	7 (17)	7 (37)	0.11
False negatives, $n$ (%)	2 (5)	1 (5)	1.00

μCi microcuries, IQR interquartile range

Two patients (5%) in the SC group and 1 (5%) in the TL group experienced early failure in the regional nodal basin that was previously investigated by SLNB technique, indicating a false-negative test result (P = 1.00). There were no adverse events encountered in either group.

Discussion

SLNB has emerged as an important tool for identifying occult regional nodal metastasis when managing patients with node negative cutaneous melanoma and oral mucosal squamous cell carcinoma [7, 8]. There has been significant interest in ^99mTc-tilmanocept (TL) as a new radiopharmaceutical agent that may improve performance characteristics of SLNB for patients with cutaneous melanoma. Notwithstanding this enthusiasm, data directly comparing SC and TL for cutaneous head and neck malignancies are lacking.

In this retrospective analysis of 60 patients with head and neck cutaneous melanoma and clinically negative regional nodal basin, undergoing SLNB, the number of hotspots, nodal basins, and hotspots per basin was similar between the SC and TL cohorts. Intraoperative variables including the differences in operative duration, radiation dose exposure, number of SLNs per patient, and frequency of SLN identification were not statistically significant, between the two groups. The frequency of false-negative SLNB was comparable between the two groups. These results suggest equipoise regarding value of SC versus TL as the radiopharmaceutical of choice when performing SLNB in patients with head and neck cutaneous melanoma and should offer pause to clinicians and institutions when considering a change in their clinical practices.

While there are no other data that examine this question specifically for patients with head and neck cutaneous melanoma, in an analysis of a consecutive case series of patients with melanoma published by Silvestri and colleagues, they reported no difference in false-negative rates between SLNB performed using SC or TL, which parallels the results from our analyses [9]. In contrast with our findings, they found that patients in the TL group had a reduction in radiation dose and number of nodes removed. However, in their cohort, patients with head and neck melanoma constituted 11.4% of all patients, and therefore, the findings from their study may not readily translate to patients with head and neck cutaneous melanoma. Other factors that may account for these differences may also include the routine use of blue dye in addition to radiopharmaceuticals in their case series. By contrast, our clinical practice patterns do not utilize blue dye for head and neck cutaneous melanoma due to concerns related to tattooing and visible blue staining in the head and neck region. Additionally, in a mixed cohort of patients with truncal and head and neck cutaneous melanoma, Eckhoff et al. reported that the number of SLNs identified and frequency of false negatives were not statistically different between SLNBs performed using SC or TL. These findings parallel those in our study; however, their results should be interpreted with caution since the majority of study subjects had truncal melanoma [10].

SLNB in the head and neck may present certain challenges due to several factors unique to the region. For example, the lymphatic drainage patterns in the head and neck are highly variable and difficult to predict due to a high density of lymph nodes in the head and neck and the multiple lymphatic channels in close proximity that may drain in an arborescent pattern to multiple (ipsilateral, contralateral, or bilateral) nodal basins [11–14]. Additionally, the short distance from the primary injection site to the draining nodal basin may heighten the problems related to the “shine-through” phenomenon and may hinder the SLNB [15]. TL may purportedly improve on some of these limitations, and therefore, it has been considered to be an attractive alternative to the traditionally used SC and has been explored as an agent for performance of SLNB for cutaneous malignancies, oral squamous cell carcinoma, and others [4, 6]. However, in our study, we did not find TL to be superior to SC with regard to any of the studied test performance characteristics related to SLNB for cutaneous melanoma of the head and neck. Similar findings have been observed by others in comparative studies, including one randomized trial, for SLNB for breast adenocarcinoma, underlining the significance of maintaining clinical equipoise when selecting SC or TL as the preferred agent for SLNB [16, 17].

The only study relating to the use of TL for SLNB in the head and neck region comes from a multicenter, non-randomized single-arm trial for oral head and neck squamous cell carcinoma (OCHNSCC) [4]. In this study, patients with T1–T4, N0, and M0 OCHNSCC received peri-lesional TL, followed by lymphoscintigraphy, SLNB, and immediate elective neck dissection. TL identified SLNs in 97.6% of patients and yielded a false-negative rate of 2.6%. A false negative was defined as a negative SLNB but positive pathology from the immediate elective neck dissection specimen. However, results from this study may not be valid for application for patients with cutaneous melanoma of the head and neck region because of differences in histology and sites of involvement.

In the absence of clear data suggesting superiority of TL over SC, clinicians and healthcare systems must consider whether utilization of TL adds value to patient care. Indeed, TL may be nearly seven times more expensive than SC [9]. If the test performance of TL remains comparable to SC, then higher costs may indeed make TL an inferior radiopharmaceutical agent, unless cost reduction or additional data emerge that support routine use of TL for SLNB in patients with head and neck cutaneous melanoma.

Limitations to this study include its retrospective nature, experience limited to a single center, non-randomized study design, the serial nature of the subjects undergoing SLNB (all procedures using SC preceded those using TL), and a lack of a priori power analyses. Additionally, it was not possible to distinguish time specifically for SLNB from the total operative duration. Due to the retrospective nature of the study, it was not possible to perform a comprehensive cost analysis.

Conclusion

In this study, for patients undergoing SLNB for cutaneous melanoma of the head and neck region, there were no statistically significant differences in the number of SLNs excised per patient, the rate of intraoperative SLN localization, the frequency of false-negative results, the operative duration, the dose of radiation exposure, or the frequency of patients with positive SLNs between the SC and TL groups. These results should spur additional comparative effectiveness trials that may investigate the value of ^99mTc-tilmanocept over ^99mTc-sulfur colloid in this specific clinical application and patient population.

Author Contribution

N. R. S.: conception and design of work; acquisition, analysis, and interpretation of data; drafting or revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

J. S.: conception and design of work; acquisition, analysis, and interpretation of data; drafting or revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

C. J.: acquisition and analysis of data; revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

A. W.: acquisition and analysis of data; revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

R. L.: conception of work; interpretation of data; revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

H. S.: design of work; analysis and interpretation of data; drafting or revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

A. M.: analysis and interpretation of data; drafting or revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

W. L.: conception of work; interpretation of data; revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

A. H.: analysis and interpretation of data; revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

O. M.: conception of work; interpretation of data; revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

A. C.: analysis and interpretation of data; revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

A. O.: analysis and interpretation of data; revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

A. P.: conception and design of work; acquisition, analysis, or interpretation of data; drafting or revising the work for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Declarations

Conflict of Interest

The authors declare no competing interests.

Disclaimer

The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

Jeffrey Schafer is a military service member. This work was prepared as part of his official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.