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doi: 10.29271/jcpsppg.2025.01.89ABSTRACT
Objective: To determine the impact of hybrid SPECT/CT lymphoscintigraphy in sentinel lymph node (SNL) detection through comparison with planar lymphoscintigraphy in breast carcinoma.
Study Design: A cross-sectional study.
Place and Duration of the Study: Department of Nuclear Medical Centre, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from July 2022 to July 2023.
Methodology: A total of 118 female patients between 26 and 79 years of age with stage 0-2 invasive ductal carcinoma of the breast referred for sentinel lymphoscintigraphy were included in the study. A non-probability sampling technique was employed for patient selection. These patients were further categorised into three groups: those with palpable tumours, those with non-palpable tumours, and those who were post-lumpectomy. Each patient underwent imaging through planar followed by SPECT/CT lymphoscintigraphy. Data were analysed using SPSS version 27. Continuous data were presented as means and standard deviations, while categorical data were presented as frequencies and percentages. Diagnostic performance metrics and Cohen’s Kappa were calculated to measure the agreement of both techniques.
Results: The mean age of all patients was 54.1 ± 11.8 years (range: 26-79 years). Among 118 patients, planar lymphoscintigraphy identified 183 suspicious hot nodal sites in 101 (85.6%) patients, whereas SPECT/CT lymphoscintigraphy identified 209 suspicious hot nodes in 115 (97.5%) patients. Both techniques detected hot nodes in 101 (85.6%) patients. The planar lymphoscintigraphy failed to detect hot nodes in 17 (14.4%) patients, while SPECT/CT was negative in three (2.5%) patients. A weak but statistically fair agreement (Kappa = 0.268, p = 0.003) was observed between the two modalities.
Conclusion: SPECT/CT offered added benefit in detecting hot lymph nodes missed by planar lymphoscintigraphy, locating identified lymph nodes, and excluding suspicious non-nodal false-positive sites.
Key Words: Breast cancer, Lymphoscintigraphy, Planar scintigraphy, Sentinel node, SPECT/ CT.
INTRODUCTION
According to the WHO, over 450,000 cases of breast carcinoma were reported in 2012, constituting more than 28% of all malignancies affecting women. The key risk factors for breast carcinoma include gender, genetic susceptibility, prolonged estrogen, and radiation exposure.1 A recently published study from Pakistan reported that breast cancer accounts for one-third of overall cancers (approximately49.5%in women) in Karachi.2
The prognosis in breast carcinoma depends upon various factors, including timely diagnosis, type of tumour, staging, and treatment options selected. With the development of breast awareness programmes, proper self-examination, and yearly mammography, detecting carcinoma at early stages would limit the need for more exploratory surgeries.
The axilla is the main site of drainage of breast tumours. Axillary lymph nodes are classified both surgically and anatomically. Generally, in lymphoscintigraphy, the surgical classification of axillary lymph nodes is used. Sentinel lymph nodes (SLNs) directly receive lymph drainage from the tumour site. If the histopathology of this node shows no metastasis, there is a high likelihood that the remaining lymph nodes in its following pathway are also free from nodal metastasis. Thus, extracting only the sentinel node dismisses the requirement for complete lymph node dissection, thereby decreasing lymphedema- related complications and improving patients’ quality of life. If two or more SLNs are identified, all nodes with significant radiotracer activity should be removed and sent for histopathological examination.3 The technique involves injecting a radioactive agent into breast tissue using various approaches. The tracer is drained by lymphatics to the corresponding lymph node, and the SLN is detected through lymphoscintigraphy using a gamma camera.
Technetium-99m labelled Nano-colloid is commonly used for lymphoscintigraphy. In 2013, technetium-99m labelled tilmanocept received approval from the US Food and Drug Administration (FDA) for SLN protocols in breast cancer.3 The rate of detection of SLNs through lymphoscintigraphy is 85-87% according to the published literature. With the combined approach of lymphoscintigraphy and blue dye, the rate of SLN detection increases up to 100%.4-6 Lymph nodes that stain blue after blue dye injection or show ≥10% of the ex vivo counts by gamma probe after radiopharmaceutical injection or palpated by hand are excised and sent for histopathological examination. Intra- mammary lymph nodes are not harvested on a routine basis. If some of the extracted lymph nodes are found to be positive for metastasis, further axillary lymph node dissection (ALND) is performed.5 Nuclear medicine departments mostly employ planar scintigraphy for SLN detection, which makes spatial localisation difficult and is challenging to interpret due to the overlap of activity from adjacent nodal sites. Where available, SPECT/CT has been used to overcome the limitations of planar scintigraphy for accurate localisation of detected lymph nodes and to identify non-nodal foci of false-positive uptake.
This study aimed to determine the impact of hybrid SPECT/CT lymphoscintigraphy in SLN detection through comparison with planar lymphoscintigraphy in breast carcinoma patients.
METHODOLOGY
The study employed a non-probability consecutive sampling method for patient selection. The WHO sample size calculator was used to calculate the sample size for this study, using a 95% confidence level and a 6% margin of error. Based on a population proportion of locally advanced breast cancer (LABC) of 11.7%, the required sample size was calculated to be 111 patients. Ethical approval was obtained from the Institutional Review Board of the Armed Forces Institute of Pathology, Rawalpindi, Pakistan. Patients who were referred for sentinel scintigraphy during the study duration, and who met the inclusion criteria, were included in the study. Informed written consent was taken from all the patients. Detailed history, including age, laterality, and stage of disease, was noted. On clinical examination, patients were divided into three groups: palpable tumours, non-palpable tumours, and post-lumpectomy.
This study included 118 women with early-stage breast carcinoma (T0–2), without regional lymph node metastases (N0) or distant spread (M0). Pregnant females and those who had prior axillary surgery were excluded.
SLN lymphoscintigraphy requires minimal patient preparation, with recommendations to remove jewellery and wear loose clothing. A human serum albumin (HSA)-based kit (NanotopPolatom, Poland) with particle sizes of 50-80 nm was used. The radiotracer, Technetium-99m, was prepared from a freshly eluted Mo-99/Tc-99 generator, with a total administered dose of 37 MBq (1 mCi) over two days or 18.5 MBq (0.5 mCi) for a single-day protocol, adhering to as low as reasonably achievable (ALARA) principles. Periareolar intradermal injections at the 6 and 12 o’clock positions were administered, followed by a gentle massage to enhance lymphatic flow.
Planar images were obtained 15 minutes after injection using a cobalt-57 flood source, which improves localisation by giving body contour.7 Planar lymphoscintigraphy was followed by SPECT-CT emission/transmission study using a hybrid system composed of a dual-head variable angle planar gamma camera with SPECT/CT using low energy high resolution (LEHR) collimator. Images obtained from both techniques were analysed separately. In order to elucidate differences in lymphatic drainage, the published literature has performed statistical evaluations of aggregated planar and SPECT/CT data.8
Data were analysed using the SPSS version 27. Continuous data were presented as means and standard deviation, while categorical data were presented as frequencies and percentages. Frequencies were compared for associations using the Fisher’s exact test. The Cohen’s Kappa was calculated to measure the agreement of both tests. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of planar lymphoscintigraphy were calculated using SPECT/CT as a reference method using online MedCalc statistical software. A p value of ≤0.05 was considered statistically significant, with analyses conducted at a 95% confidence interval.
RESULTS
The average age of all patients was 54.1 ±11.8 years (range: 26-79 years). Seventy-eight (66.1%) patients were diagnosed at stage 2A, followed by 31 (26.3%) patients at stage 2B. Early- stage detection (IA and IB) was seen only in 9 (7.6%) patients. Tumour laterality was evenly distributed between the right breast involvement in 57 (48.3%) patients, and the left breast involvement in 59 (50.0%) patients, and bilateral in only 2 (1.7%) patients.
Among 118 patients, planar lymphoscintigraphy identified 183 hot nodal sites in 101 (85.6%) women. SPECT/CT lymphoscintigraphy identified 209 hot nodal sites in 115 (97.5%) women. Both techniques detected hot nodes in 101 (85.6%) women. The planar lymphoscintigraphy was negative in detecting hot nodes in 17 (14.4%) women, while SPECT/CT was negative in three (2.5%) women.
Table I: Comparison of levels of sentinel lymph nodes detection by both techniques.
|
Levels |
PLANAR SLNs |
SPECT-CT SLNs |
|
Positive (n = 101) |
Positive (n = 115) |
|
|
Level 1 |
84 |
98 |
|
Level II |
3 |
3 |
|
Level 1, II |
10 |
10 |
|
Level I, II, III |
2 |
2 |
|
Level I and intramammary |
2 |
2 |
Table II: Association between clinical groups and detection of sentinel lymph nodes by planar and SPECT/CT lymphoscintigraphy.
|
Clinical groups |
SPECT/CT SLNs |
p-values |
|||
|
Positive |
Negative |
||||
|
Palpable tumours |
Planar SLNs |
Positive |
78 |
0 |
0.133 |
|
Negative |
11 |
1 |
|||
|
Total |
89 |
1 |
|||
|
Non-palpable tumours |
Planar SLNs |
Positive |
14 |
0 |
-* |
|
Negative |
1 |
0 |
|||
|
Total |
15 |
0 |
|||
|
Post-lumpectomy |
Planar SLNs |
Positive |
9 |
0 |
0.077 |
|
Negative |
2 |
2 |
|||
|
Total |
11 |
2 |
|||
|
§ Fisher’s Exact test. *No statistics were computed because SPECT/CT lymphoscintigraphy is constant in the positive group. |
|||||
Table III: Diagnostic agreement between planar and SPECT/CT lymphoscintigraphy.
|
|
SPECT/CT positive |
SPECT/CT negative |
Total |
|
Planar positive |
101 (True positive) |
0 (False positive) |
101 |
|
Planar negative |
14 (False negative) |
3 (True negative) |
17 |
|
Total |
115 |
3 |
118 |
|
Agreement measure (Cohen’s Kappa): 0.268. Standard error: 0.125; Approximate T: 4.277, p-value: 0.003. |
|||
Figure 1: Bar chart showing comparison of planar and SPECT/CT.
Both imaging methods showed that most SLNs were located in level 1. Detection at higher levels (Level II, Level 1 and II, Level I, II, and III, and Level I and intramammary) remained consistent between both modalities, suggesting that SPECT/CT enhances level 1 identification but does not significantly improve detection at deeper levels (Table I).
In patients with palpable tumours (n = 90), planar imaging detected SLNs in 78 (86.6%) cases, while SPECT/CT detected SNLs in 89 (98.8%) cases, missing only one case. Among women with non-palpable tumours (n = 15), planar detected SLNs in 14 (93.3%) patients, while SPECT/CT detected SLNs in all 15 patients (100%). For the post-lumpectomy group (n = 13), planar detected SLNs in nine patients, whereas SPECT/CT was able to detect SLNs in all 13 patients, including the four missed by planar imaging. Despite SPECT/CT identifying more SLNs across all groups, there was no statistically significant difference in detection between the two imaging techniques across the clinical categories (p>0.05), as shown in Table II.
There was a weak but statistically fair agreement between planar and SPECT/CT lymphoscintigraphy in SLNs detection (Kappa = 0.268, p = 0.003, Table III). SPECT/CT lympho-scintigraphy identified 115 SLNs, whereas planar lympho-scintigraphy identified 101, with 14 (11.8%) cases missed by planar imaging, as shown in Table III and Figure 1. However, the planar yielded sensitivity and specificity of 87.8% (95%CI: 80.4-93.2%) and 100% (95%CI: 29.2-100%), respectively, with a diagnostic accuracy of 88.1% (95%CI: 80.9-93.4%). PPV and NPV were 100% (95%CI: 96.4-100%) and 17.6% (95%CI: 3.8-43.4%), respectively, while having SPECT-CT as a reference method for SLN detection.
DISCUSSION
Planar lymph scintigraphy is a useful technique to provide a guide for surgeons by tracing the direct lymphatic pathway from the tumour site to the SLN. Evaluation of lymphatic channels is easier in superficial malignancies such as breast carcinoma, as compared to deep malignancies e.g. gastrointestinal malignancies.9
According to the European Association of Nuclear Medicine (EANM) 2019’s guidelines, Nano-colloid dose recommendation for a single-day protocol is 40-50 Mega Becquerel (MBq), which is 1.08-1.35 milliCurie (mCi), whereas for a two-day protocol, 70-120MBq (1.89-3.24 mci) should be injected. In this study, the authors performed with almost half of the recommended dose and visualised SLNs as well as enough intraoperative gamma probe counts according to the surgeons.
Regarding injection techniques, various approaches have been practised, each with its own advantages and disadvantages. Numerous studies showed that dermal, subdermal or sub areolar approaches could improve SLN identification rates and decrease the false-negative rates.10 Lerman et al. reported that shine-through is a major drawback of peritumoural injection in patients with tumours located in the outer quadrant, and therefore, adopted the periareolar technique.8 The periareolar intradermal injection approach was applied in this study. Several factors can impact the visualisation of the SLNs during lymphoscintigraphy. Siddique et al. stated that tumour cells progressively infiltrate lymphatics, limiting the radiotracer transport.11 In the present study, both techniques failed to detect hot nodes in three patients, which were seen in the Post-lumpectomy group. There are various methods to improve the planar technique. Ohtake et al. suggested that altering the colloid particle concentration, varying the amount of radiotracer, choosing different imaging times (early versus delayed), administering a second injection of the radiopharmaceutical, and applying post-injection massage may increase the detection rate of sentinel nodes.12 Post-injection massage was also carried out in this study. The preoperative use of SPECT/CT for the identification of SLNs is not only important for the additional number of SLNs, but also for the capability of providing anatomical information. Quartuccio et al. stated that nonspecific hot areas/spots, which are visualised on planar scintigraphy, are easily localised on SPECT/CT.13 In this study, both techniques were performed on patients the day before the surgery was planned. The planar lymphoscintigraphy was negative in detecting hot nodes in 17 women, while SPECT/CT was negative in three women. SPECT/CT detects more SLNs than planar, but the number of SLNs has no significant impact on metastasis detection.14 Nakano et al. stated that the gamma scintillation probe has shown a high intraoperative detection rate (over 94%).15 Olmos et al. stated that the planar scintigraphy was falsely-negative more in obese patients than the general population, which was 28%.16 Previous reports have discussed the methodologic details for optimising lymphoscintigraphy, recommending acquisition of early images, the use of high-resolution collimation, multiple projections, and the use of markers and transmission images with a cobalt-57 flood source to facilitate anatomic localisation.17 In this study, a cobalt-57 phantom was used to further form the body contour. Preoperative SLN localisation through SPECT/CT would reduce the scope of surgical resection, which is important for breast-conserving surgery.18-20 Ghfir et al. stated that delaying the imaging time interval increased the rate of detection of lymph nodes, which was up to 85%.21 Two SLNs with close proximity and very faint activity due to deeply located lymph nodes can be appreciated well by SPECT/CT. van der Ploeg et al. stated that SPECT/CT also differentiates between nodal and extra-nodal hot spots, such as radioactive spillage or skin contamination.22
There are certain limitations to this study. This is a single- centre study with a limited number of patients. Due to the availability of one hybrid SPECT/CT system in the department, the time between planar and SPECT/CT acquisitions varied on any particular day, which may have potentially affected the interpretation. However, both studies were acquired within two hours of each other. Accuracy of both planar and SPECT/CT SLN imaging could not be determined due to the non-availability of histopathological reports in the majority of enrolled patients.
CONCLUSION
SPECT/CT provided an added benefit in detecting hot lymph nodes missed by planar lymphoscintigraphy, localisation of detected lymph nodes, and exclusion of suspicious non- nodal false-positive sites.
ETHICAL APPROVAL:
Ethical approval was obtained from the Institutional Review Board of the Armed Forces Institute of Pathology, Rawalpindi, Pakistan (FC-NMC21-24/READ-IRB/22/1283).
PATIENTS’ CONSENT:
Written informed consent was taken from all the patients.
COMPETING INTEREST:
The authors declared no conflict of interest.
AUTHORS’ CONTRIBUTION:
RF: Conception, study design, data acquisition, and drafting of the work.
RS: Data acquisition, drafting of the work, and critical revision of the manuscript.
FH: Conception, study design, data acquisition, analysis, and critical revision.
ZSD: Data acquisition, analysis, drafting of the work, and critical revision.
AM: Study design, interpretation of the data, and critical revision.
MR: Data acquisition and analysis.
All authors approved the final version of the manuscript to be published.
REFERENCES