Ann Nucl Med DOI 10.1007/s12149-014-0821-1
SHORT COMMUNICATION
Lymphoscintigraphy in early-stage non-small cell lung cancer with technetium-99m nanocolloids and hybrid SPECT/CT: a pilot project Jonathan T. Abele • Karen Allred • Tracey Clare Eric L. R. Be´dard
•
Received: 26 November 2013 / Accepted: 5 February 2014 Ó The Japanese Society of Nuclear Medicine 2014
Abstract Objective The goal of our study was to determine if lymph node activity could be visualized using a hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) scanner with two commonly used colloidal lymphatic radiotracers—99mTc-antimony sulfide colloid (ASC) and 99mTc-filtered sulfur colloid (FSC) in the setting of low-stage non-small cell lung cancer (NSCLC). Methods Patients undergoing CT-guided percutaneous lung biopsies for clinically suspected early-stage lung cancer were randomized to peri-lesional injection of 37 MBq (0.5 mL) of either ASC or FSC. SPECT/CT of the thorax was performed at either 1, 2, or 3 h post-injection. The images were reviewed to determine if lymph node activity separate from the injection site could be identified. Results 24 patients were included. Lymph node activity was identified in 50 % of patients. A total of 15 lymph nodes with activity were visualized including 5 ipsilateral
A portion of this data was previously presented orally at the Canadian Association of Nuclear Medicine Annual Scientific Meeting 2012 (Ottawa, Ontario). J. T. Abele (&) T. Clare Department of Radiology and Diagnostic Imaging, University of Alberta, 8440-112 St., 2A2.41 WMC, Edmonton, AB T6G 2B7, Canada e-mail:
[email protected] K. Allred Department of Nuclear Medicine, Royal Alexandra Hospital, Edmonton, AB, Canada E. L. R. Be´dard Division of Thoracic Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
hilar, 6 ipsilateral mediastinal, and 4 distant locations. No contralateral mediastinal or hilar activity was visualized. There was a tendency to improved visualization with ASC and the longer 3 h wait time. Most patients also demonstrated significant pleural, tracheobronchial, and/or systemic activity. Conclusions SPECT/CT imaging can demonstrate lymph node activity separate from the injection site in at least some low-stage NSCLC patients with a perilesional injection of 99mTc nanocolloid tracers. Further investigation into the role of pre-operative lymphoscintigraphy with SPECT/CT in patients with lung cancer is warranted. Keywords Lymphoscintigraphy Lung cancer SPECT/CT
Introduction Lung cancer remains the primary cause of cancer-related deaths worldwide with an overall 5-year survival rate of 15 % [1, 2]. Despite modern treatment techniques, even earliest-stage non-small cell lung cancer (NSCLC)—stage IA—has a 5-year survival rate of only 67 % [3]. One of the possible causes of these statistics is that patients are understaged by the current staging methods. Accurate staging of lymph node status is the most important prognostic factor in localized NSCLC [4–6]. While commonly used in the evaluation of other malignancies such as breast cancer and malignant melanoma, sentinel lymph node (SLN) identification and biopsy are not routinely performed for lung cancer. Accurate identification of the SLN in lung cancer would not only decrease the operating time, costs, and potential complications associated with more extensive nodal dissection, but more
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importantly would also allow dedicated intensive pathologic analysis of these specific nodes [2]. This may result in more accurate staging, better treatment, and perhaps improved survival particularly for early-stage NSCLC. Previous studies attempting to identify the SLN in lung cancer have utilized isosulfan blue dye, gamma probe techniques (in vivo and ex vivo), and 2-dimensional planar imaging techniques with limited success [2, 7, 8]. Surprisingly, given the known complex pattern of lymphatic drainage in the thorax, the use of 3-dimensional SPECT imaging has been sparse [3, 5, 8]. To our knowledge there have been no previous reports attempting to identify the SLN in lung cancer using modern hybrid SPECT/CT camera systems. The goal of our study was to determine if lymph node activity separate from the injection site could be identified using a hybrid SPECT/CT scanner with two commonly used colloid lymphoscintigraphy radiotracers—99mTcantimony sulfide colloid (ASC) and 99mTc-filtered sulfur colloid (FSC). If possible, further development may lead to the utilization of SPECT/CT in pre-operative SLN localization.
Methods Patients referred to the diagnostic imaging department at our institution for CT-guided percutaneous biopsy of a suspected stage 1 lung cancer between December, 2010 and June, 2012 were considered for inclusion. Those meeting the inclusion and exclusion criteria (Table 1) were approached for enrollment. Informed consent for study participation was obtained from all participants. The study
protocol was reviewed and approved by our institutional research ethics board. CT-guided radiotracer injection A CT-guided percutaneous lung biopsy was initially performed using a standard co-axial technique. This involved the initial introduction of a 19 G guiding needle. While the tip of the guiding needle was typically placed at the outer edge of the lesion, the exact placement was determined by the radiologist performing the procedure based on clinical preference. Subsequent fine needle aspiration with a 22 G needle and/or core biopsy with a 20 G needle through the guiding needle was then performed. Real-time evaluation of the samples by a cytotechnologist to determine the adequacy of sampling was performed. Once adequate sampling was obtained, the sampling needles were withdrawn and radiotracer was injected into the perilesional region through the guiding needle. The guiding needle was then removed. Radiotracer A single injection of 0.5 mL of radiotracer was injected per patient. The type of radiotracer injected was either 37 MBq (1 mCi) of ASC or 37 MBq (1 mCi) of FSC. The type injected was determined by a nuclear medicine technologist without knowledge of the patient based on tracer availability within the department on a given day as well as a goal to ultimately have similar numbers of each radiotracer type. The radiologist injecting was blinded to the type of radiotracer injected. SPECT/CT imaging
Table 1 Inclusion and exclusion criteria Inclusion criteria
Exclusion criteria
Clinically suspected stage IA or IB non-small cell lung cancer (1–5 cm, N0, M0)
Lesion \1 or [5 cm in diameter
Age C50 years
Nodal enlargement on CT (hilar [5 mm SAD, mediastinal [10 mm SAD, subcarinal [15 mm SAD) Previous diagnosis of lung cancer Previous thoracotomy Previous thoracic radiotherapy Evidence of chest wall or mediastinal invasion on CT Pregnant Age \50 years Previous mediastinoscopy
SAD maximal short axis diameter
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The patients were then transferred to the diagnostic imaging recovery room for standard post-biopsy clinical care. Patients were initially randomized to SPECT/CT imaging at 1 or 2 h post-injection. For the final 4 patients, SPECT/ CT imaging was performed at 3 h post-injection. SPECT/CT imaging was performed using a Philips Precedence 16-slice SPECT/CT camera system (Philips Healthcare, Andover, MA, USA). The SPECT protocol included a single bed position acquisition through the chest (including from the top of shoulders through the bottom of the diaphragm). The SPECT acquisition parameters included: acquisition time 20 s per frame, number of frames 128, photopeak 140 keV with 20 % window, matrix 128 9 128, collimator XGP. A non-breath-hold CT scan of the same anatomic region was also performed without IV contrast. The CT acquisition parameters included: mAs 70, kVp 120, slice thickness 5 mm reconstructed at 2.5 mm intervals, field of view 600 mm, matrix 512 9 512. The
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SPECT images were reconstructed using ASTONISH iterative reconstruction (4 iterations, 16 subsets, uniform start, decay correction applied) with CT-based attenuation correction. Image review All reconstructed images were reviewed using Fusion Viewer software on Extended Brilliance Workstation platforms (Philips Healthcare, Andover, MA, USA). Both fused as well as non-fused SPECT and CT images were assessed in transverse, coronal, and sagittal planes. The images were scaled to maximize sensitivity for activity above background outside of the injection site. Data recorded included: lymph node activity, pleural activity, tracheobronchial activity (trachea or mainstem bronchi), visible extrathoracic activity, the site of injection relative to the lesion, the distance of the injection site to the chest wall, and the presence or absence of any pneumothorax. Clinical use of data The data were used solely to determine imaging feasibility. The data were not provided to the involved surgeons and did not impact routine clinical care.
Results Twenty-four patients were included (13 male, 11 female). The average age was 66.8 years (range 54–81). The average lung lesion size was 2.7 cm (range 1.2–5.0 cm). Lobar distribution of the biopsied lesions included left upper lobe in 9 patients, left lower lobe in 4 patients, right upper lobe in 8 patients, right middle lobe in 0 patients, and right lower lobe in 3 patients. Ten (10/24) had tracer injected within the lesion. Twelve (12/24) patients had tracer injected along the lateral margin of the lesion. Two (2/24) patients had tracer injected near the chest wall (lesions abutted the chest wall). All lesions were located peripherally and the distance from the injection site to the chest wall averaged 2.7 cm (range 0–4.2 cm). A total of 12 patients were injected with ASC and 12 patients were injected with FSC. The time delay from injection to imaging was 1 h (average 63.4 min, range 57–80 min) for 11 patients (5 ASC, 6 FSC); 2 h (average 124.4 min, range 109–138 min) for 9 patients (5 ASC, 4 FSC); and 3 h (average 187.5 min, range 180–205 min) for 4 patients (2 ASC, 2 FSC). Lymph node activity was identifiable in 12/24 (50 %) patients with a total of 15 active lymph nodes (3 patients demonstrated activity in 2 lymph nodes). Longer wait times
between injection and imaging demonstrated improved lymph node visualization with 4/11 (36 %) of patients imaged at 1 h demonstrating lymph node activity, 4/9 (44 %) of patients imaged at 2 h demonstrating lymph node activity, and 4/4 (100 %) of patients imaged at 3 h demonstrating lymph node activity. Lymph nodes were visible in 7/12 (58.3 %) of patients injected with ASC. Lymph nodes were visible in 5/12 (41.7 %) of patients injected with FSC. Lymph node locations with visible activity included ipsilateral hilar (5/15 lymph nodes), ipsilateral mediastinum (6/15), and distant (4/15). No activity within contralateral hilar or mediastinal lymph nodes was visualized. The ipsilateral mediastinal locations included the tracheobronchial angle (2/15; AJCC station 4R and 4L), AP window (2/15; AJCC station 5), and subcarinal (2/15; AJCC station 7) (Fig. 1). The distant locations included the internal mammary chain (2/15), the retrocrural space (1/ 15), and the gastrohepatic ligament (1/15) (Fig. 2). Most patients (18/24; 75 %) demonstrated evidence of activity within the pleural space, and in most cases this was diffusely distributed (Fig. 3). Activity was identifiable within the tracheobronchial tree (trachea or mainstem bronchi) in 4/24 (17 %) (Fig. 4). Activity was identifiable within the liver and spleen in 5/24 (21 %) implying at least some systemic distribution of activity in these patients. Fifteen (15/24) patients were shown to have at least a small pneumothorax on SPECT/CT imaging. Final pathology results yielded a diagnosis of non-small cell lung carcinoma in 16 patients (16/24; 67 %) including adenocarcinoma (8), squamous cell carcinoma (3), neuroendocrine tumor (1), and non-specific (4). Other diagnoses included metastatic adenocarcinoma from colon primary (1), hamartoma (1), nodular amyloid (1), atypical cells (1), inflammatory cells (2), and non-diagnostic (2). Data collected for each patient are summarized in Table 2.
Discussion Our pilot project study represents the first report using a hybrid SPECT/CT scanner and 99mTc-labeled nanocolloids in an attempt to assess lymphatic drainage in patients with early-stage NSCLC. While 99mTc ASC and FSC with SPECT/CT imaging are commonly used to identify the SLN in the setting of breast cancer, malignant melanoma, and a variety of other tumors, there have been no reports in the setting of lung cancer to date [9, 10]. In particular, we were interested in whether distinct lymph node activity separate from the injection site could be identified. If possible, this technique may lead to the future development of using SPECT/CT in the pre-operative identification of
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Fig. 1 Transverse and sagittal fused SPECT/CT images from patient #2 (LUL injection of ASC, 1 h from injection). Arrow A delineates location of activity within the left suprahilar lymph node (11L). Arrow B delineates the injection site
Fig. 2 Transverse and coronal fused SPECT/CT images from patient # 21 (RUL injection of ASC, 3 h from injection). Arrow A delineates activity within a gastrohepatic lymph node
Fig. 3 Coronal and sagittal fused SPECT/CT images from patient # 7 (RLL injection of FSC, 1 h from injection). Activity is seen distributed diffusely throughout the pleural space (visualized in 75 % of patients). Cross-hair demonstrates site of triangulation
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Fig. 4 Transverse and coronal fused SPECT/CT images from patient # 8 (LUL injection of ASC, 1 h from injection). Activity is demonstrated within the left mainstem bronchus
Table 2 Detailed patient characteristics Pt #
Age
Sex
Lobe
Size (cm)
Tracer
1
58
F
RUL
3.6
ASC
2
61
M
LUL
1.4
ASC
3
77
M
LUL
2.1
4
65
F
RLL
5
62
M
6
57
M
7
69
8
Time (min)
LN
Pleura
TB
L/S
61
4R
Y
N
N
58
11L
N
N
N
ASC
123
11L
Y
Y
Y
2.0
FSC
119
None
Y
N
N
RUL
2.9
FSC
57
None
Y
N
N
LLL
2.8
FSC
60
RC
Y
N
N
M
RLL
3.1
FSC
63
None
N
N
Y
54
M
LUL
2.1
ASC
80
None
N
Y
N
9
81
F
LUL
1.9
FSC
109
7
Y
N
Y
10
71
M
RUL
4.4
FSC
120
None
N
Y
N
11
72
F
LUL
2.2
FSC
70
None
Y
N
N
12
67
F
RUL
1.2
ASC
60
None
Y
N
N
13 14
71 76
M F
RUL LUL
3.4 2.4
ASC FSC
137 63
IM None
Y Y
N N
N N
15
64
F
RLL
3.6
FSC
135
None
N
N
N
16
75
M
LLL
3.0
FSC
65
11L, 5
Y
N
N
17
62
M
RUL
1.4
ASC
60
None
Y
N
N
18
81
F
LUL
2.3
ASC
120
None
Y
N
N
19
67
M
RUL
3.2
ASC
138
11R, 11R
Y
Y
N
20
63
F
LLL
2.7
ASC
119
None
N
N
N
21
69
F
RUL
4.0
ASC
180
GH, IM
Y
N
N
22
62
M
LUL
4.0
ASC
185
4L
Y
N
Y
23
64
M
LLL
5.0
FSC
180
7
Y
Y
N
24
56
F
LUL
1.3
FSC
205
5
Y
N
N
99m
Pt patient, F female, M male, RUL right upper lobe, LUL left upper lobe, RLL right lower lobe, LLL left lower lobe, ASC Tc-antimony sulfide colloid, FSC 99mTc-filtered sulfur colloid, Time time from tracer injection to SPECT/CT imaging, LN lymph node activity and station, 4R right tracheobronchial angle, 11L left hilar, RC retrocrural, 7 subcarinal, IM internal mammary, 5 aortopulmonary window, 11R right hilar, GH gastrohepatic, 4L left tracheobronchial angle, Pleura pleural activity, TB tracheobronchial activity, L/S liver/spleen activity
the SLN in lung cancer. Pre-operative imaging with SPECT/CT has the potential to improve SLN localization (particularly for patients with atypical drainage patterns or with the SLN outside of the surgical field), decrease operating time, decrease patient morbidity, and improve
the accuracy of pathological analysis resulting in improved staging, therapy, and outcome. Lymph node activity separate from the injection site was identifiable in 50 % of patients in a variety of hilar, mediastinal, and distant locations. While there is no direct
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evidence that these represent the SLN related to the lung cancer, in most cases these lymph nodes were solitary (1 lymph node visualized in 9 patients; 2 lymph nodes visualized in 3 patients) likely reflecting early nodal drainage from the injection site. As such, our study demonstrates that SPECT/CT is a technology requiring further exploration for this indication. The rate of lymphatic migration with ASC and FSC is unknown in the lungs. Thus, the optimal imaging time from injection to SPECT/CT is unknown in this setting. In cases of sentinel lymphoscintigraphy in other areas of the body, dynamic planar imaging is often performed initially until a suspected lymph node is identified after which SPECT/CT may be performed to improve localization. Dynamic imaging could not be performed in our study due to the absence of gamma cameras in the diagnostic imaging recovery room. Given this uncertainty, patients were divided into different colloidal tracer sizes (ASC 10 nm versus FSC 50–220 nm) and different times from injection to SPECT/CT imaging (1, 2, or 3 h) in an attempt to visualize lymph nodes in at least some patients. While statistical significance cannot be determined given the small size of our pilot project population, there was a trend toward increased LN identification using a smaller-sized tracer (ASC) as well as the longer time to imaging (3 h). In fact, LN activity was visualized in all 4 patients with a time from injection to SPECT/CT imaging of 3 h, regardless of tracer type. Focal lymph node activity was not visualized in 50 % of patients in our study. This may reflect an inadequate wait time from injection to imaging for many of these patients. While 2-dimensional planar scintigraphy has been used successfully for SLN localization in breast cancer and melanoma, it has not been successfully used in lung cancer likely due to the complex overlapping nature of the thoracic lymphatics. Surprisingly, there are few studies describing evaluation with 3-dimensional SPECT or SPECT/CT. Nomori et al. [11] reported the use of a combined SPECT/CT system for the detection of the SLN in lung cancer in 2007. Their technique differed from our project in that they used 99m Tc-labeled tin colloid (a larger molecule with slower migration through the lymphatics requiring injection 18 h prior to surgery) and manually fused separately acquired SPECT and CT images (this methodology lacks the advantages of simultaneous SPECT and CT without patient motion, CT-based attenuation correction, iterative reconstruction, and depth-dependent resolution recovery). Interestingly, Nomori et al. reported reduced sensitivity for detection of mediastinal SLNs (0.40) compared with segmental (0.87) and lobar (0.74) SLNs when compared with a gamma probe. At least a component of this difference may be technically related and would be expected to be improved with modern hybrid SPECT/CT camera systems.
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While no contralateral lymph node activity was identified, activity was demonstrated in distant lymph nodes (outside of the hilum or mediastinum) in 3 patients (4 lymph nodes total), including one within the abdomen (gastrohepatic ligament). In all 3 of these patients, no activity within the hilar or mediastinal lymph node stations was identified. It is possible that this reflects an unusual lymphatic drainage pattern in these patients. Previous reports have discussed the difficulty in identifying the SLN intra-operatively with a gamma probe in lung cancer using in vivo techniques [2, 8, 12]. This has been thought to relate to high background activity at the injection site or within the tracheobronchial tree. Our study demonstrated tracheobronchial activity in 17 % (4/24) of patients. As well, there was diffuse pleural activity in 75 % (18/24) of patients. This pleural activity may also account for a component of the previously reported high background activity, limiting successful in vivo detection with a gamma probe. The reason for this high rate of pleural activity is unknown. It is possible that it reflects actual lymphatic drainage to the pleura related to the peripheral injection or it may reflect tracking of injected activity along the percutaneous needle tract. Fifteen (15/24; 63 %) of the patients in our study demonstrated at least a tiny pneumothorax on the SPECT/ CT which presumably reflects the tracking of air. When the 3–4 h delayed chest radiographs (standard institutional post-biopsy practice) were reviewed, however, only nine (9/24; 38 %) of the patients demonstrated a pneumothorax, none of which required management with a chest tube or admission to hospital. This is in keeping with reported post-biopsy pneumothorax rates of approximately 30 % [14]. The tracheobronchial activity noted in our study implies communication between the biopsy site and airways in some patients, and the systemic liver/spleen activity noted (5/24; 21 %) implies communication between the biopsy site and pulmonary veins. Although the reported risk of tumor seeding along the needle track is low at \1 % [13], the amount of contamination of the tracheobronchial tree and systemic circulation in our study does raise questions regarding implications for tumor spread with percutaneous biopsy. There are a number of limitations to our study. While we have demonstrated the ability to visualize lymph nodes separate from the injection site with SPECT/CT, we have not determined if our injection site, tracer type, or wait time from injection to imaging is optimal. For example, recent reports of SLN identification techniques using a transbronchial approach have yielded excellent results with identification of suspected SLNs in up to 92.3 % of patients [15]. Based on this it may be useful to evaluate SPECT/CT
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imaging using 99mTc tracers with a medial peritumoral injection, possibly via a transbronchial approach. Kim et al. [16] have recently evaluated the use of 99mTc neomannosyl human serum albumin for identifying the SLN in lung cancer using both pre-operative CT-guided and intra-operative injection techniques. Using ex vivo analysis intra-operatively (the criteria for a positive excised lymph node defined as 5 times background measured with a gamma probe), they describe SLN detection rates of 95.8 and 97.1 %. While they do describe performing SPECT on these patients, they did not perform SPECT/CT and do not comment on the pre-operative lymph node identification rates with imaging. Given the reported high SLN detection rates, it would be interesting to perform dedicated SPECT/ CT of patients injected pre-operatively with this tracer to determine what fraction of SLN’s can be identified prior to surgery. If a percutaneous approach to injection is used it would be useful to better clarify the optimal time from injection to imaging. Our study suggesting a longer wait time (3 h or greater) may be best with these tracers (ASC and FSC). A larger prospective study with a standardized injection to imaging time in this range would be helpful to more accurately determine the lymph node identification rate. If possible, serial SPECT imaging may also be of value to assess lymphatic drainage in a more dynamic fashion. Importantly, our study is a feasibility pilot project to determine if lymph node activity separate from the peritumoral injection site can be visualized with SPECT/CT. Our study does not directly evaluate the accuracy of detection of the true SLN. While it is assumed that the visualized lymph nodes represent an early draining node (given only 0, 1, or 2 lymph nodes were visualized in any given patient), this has not been proven. For example, given the high prevalence of pleural activity, in some cases the visualized lymph nodes may reflect lymphatic drainage from the pleura rather than the injection site. To determine the accuracy of detection of the true SLN, prospective excision and pathologic analysis of the identified lymph node as well as a comparative more complete lymph node dissection group would be required.
Conclusion This pilot project demonstrates the ability to visualize distinct lymph node activity separate from the peri-tumoral injection site in patients with low-stage NSCLC utilizing hybrid SPECT/CT and 99mTc nanocolloids. Our study demonstrated distinct lymph node activity in 50 % of cases. Further evaluation using SPECT/CT with a larger patient group (particularly, at 3 or more hours), other tracer types, and transbronchial injection would be valuable.
Acknowledgments The authors would like to thank the Royal Alexandra Hospital CT and NM departments for their help in completing this project. This study was funded by the Canadian Society of Nuclear Medicine/General Electric Radiant Young Investigator’s Award 2010. Conflict of interest disclosed.
No potential conflicts of interest were
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