Introduction
Lymphangioleiomyomatosis (LAM), a rare multi-system disease primarily found in women, is characterized by diffuse cystic changes in the lung [
1,
2]. LAM mainly affects the lung, but can also involve the thoracic and abdominal axial lymphatics, including the lymph nodes in the pelvic cavity, retroperitoneum, mediastinum, and thoracic duct [
3]. LAM lesions are generated by the proliferation of immature smooth muscle-like cells (LAM cells) [
4]. Patients with LAM may present with dyspnea, chylous pleural effusion, pneumothorax, hemoptysis, and symptoms associated with extrapulmonary involvement [
5]. Extrapulmonary manifestations, occurring in more than 70% of patients, include angiomyolipomas (AMLs), lymphangioleiomyomas, lymphadenopathy, and lymphatic dilation [
6].
A previous retrospective study used CT lymphangiography to evaluate the lymphatic system disorder in 27 patients with LAM and observed various axial lymphatic system manifestations in the thorax and abdomen [
7]. However, nuclear medicine imaging findings of the lymphatic system disorder in LAM patients have not been described comprehensively before.
99mTc-antimony sulfide colloid (ASC) lymphoscintigraphy is a widely used method for lymphatic mapping. Until now, there has been no report of
99mTc-ASC lymphoscintigraphy findings of LAM.
68Ga-NOTA Evans Blue (
68Ga-NEB) is an albumin-binding PET radiotracer for lymphatic imaging and has been used in several lymphatic disorders for diagnosis and evaluation [
8‐
14]. We recently reported a LAM patient whose
68Ga-NEB PET/CT not only clearly displayed the lymphatic disorders in the abdomen but also unexpectedly revealed diffuse abnormal NEB activity in bilateral lungs, suggesting the existence of pulmonary lymphatic circulation abnormality [
15]. Therefore, in this current prospective study, we aimed to further evaluate
68Ga-NEB PET/CT in LAM and to compare it with
99mTc-ASC lymphoscintigraphy.
Discussion
LAM is characterized by the proliferation of LAM cells in the affected organs. LAM cells can produce VEGF-D, a lymphangiogenic growth factor [
17]. It is speculated that VEGF-D promotes the local aggregation of lymphatic endothelial cells, which then promotes the formation of lymphatics [
18]. Extensive lymphatic vessels in both pulmonary and extrapulmonary LAM lesions have already been noted and described as cystic or slit-like spaces within the LAM foci in histopathologic studies [
19‐
22]. Our finding of diffuse NEB activity in the lung on PET/CT images, suggesting the hyperplasia and dilation of pulmonary lymphatic vessels, supported the findings of these histopathologic studies. Obviously,
68Ga-NEB PET/CT is an ideal imaging method to visualize the existence of extensive lymphatic changes in the lung region.
The existence of pulmonary lymphatic abnormality in LAM is not fully acknowledged in the clinic, which is attributed to the fact that in clinical practice, the examination of lymphatic vessels in lung specimen is not routinely performed as the presence of lymphatic vessel within LAM foci is not required for the pathologic diagnosis of LAM [
23]. According to the American Thoracic Society/Japanese Respiratory Society guidelines, a definite diagnosis of LAM can be made based on the presence of cystic changes on HRCT of the chest characteristic of LAM and any of the following confirmatory features: renal AML, chylous effusion, lymphangioleiomyoma, adenopathy, lymphatic vessels dilation, and either definite or probable tuberous sclerosis complex (TSC) [
23]. If these extrapulmonary features of LAM are not evident, a lung biopsy would be required to confirm the diagnosis. Since we were able to visualize pulmonary lymphatic abnormality by
68Ga-NEB PET/CT, pulmonary lymphatic abnormality might be considered as one additional confirmatory feature of LAM to aid the diagnosis and evaluation of the disease. With
68Ga-NEB PET/CT, the confidence of diagnosis in patients, especially those found with only pulmonary cystic changes would be increased.
Extrapulmonary lymphatic system manifestations of LAM observed in our study included adenopathy, lymphatic vessel dilation, retroperitoneal and pelvic lymphangioleiomyoma, and chylous effusion. As mentioned above, these extrapulmonary lymphatic system disorders are confirmatory features of LAM, and the demonstration of these abnormalities with 68Ga-NEB PET/CT may aid the diagnosis and evaluation of the disease. Lymph adenopathy and lymphatic vessel dilation, generally presented with intense NEB activity, could be easily visualized on PET/CT images.
We also noticed that in lymphangioleiomyoma, manifested as a well-circumscribed multilocular mass with central fluid rich region on CT scan, NEB accumulation was only seen in part of the cystic components. It was reported that lymphangioleiomyoma is a result of smooth muscle cell proliferation in the lymph vessels, which then causes dilatation and obstruction in the lymph vessels and collection of chylous material [
20,
24‐
26]. Therefore, part of the cystic components may communicate with the lymphatic system, which leads to tracer accumulation.
The positive rate of
68Ga-NEB PET/CT in detecting pulmonary lymphatic disorder is significantly higher than that of
99mTc-ASC lymphoscintigraphy (
P < 0.001). Considering that NEB binds to albumin during circulation and the size of NEB/albumin complex is much smaller than
99mTc-ASCs, it is thus easier for NEB to reach the involved pulmonary lymph vessels, which are generally very small in diameter [
13,
14,
19]. A previous study reported that CT lymphangiography showed intrapulmonary lymphatic vessel dilation in 11% (3/27) LAM patients [
7]. It is also worth noting that the size of the observed dilated intrapulmonary lymphatic vessels ranged from 0.1 to 0.4 cm, raising the possibility that CT lymphangiography is able to detect relatively large lymphatic vessels but not small ones, which might explain the low positive rate (11%) of CT lymphangiography. Further studies of comparing
68Ga-NEB PET/CT and CT lymphangiography in evaluating LAM in more patients are need to confirm this finding.
In this study,
68Ga-NEB PET/CT is also more revealing than
99mTc-ASC lymphoscintigraphy by presenting more extrapulmonary lymphatic disorders. Our results demonstrated that, compared to
99mTc-ASC lymphoscintigraphy,
68Ga-NEB PET/CT showed added value in 9/10 patients for the detection of pulmonary lymphatic abnormalities, 5/10 patients for enlarged lymph nodes, 3/10 patients for dilation of the lumbar trunk and/or iliac lymph vessels, 1/10 patients for thoracic duct dilation and 1/10 patients for lymphangioleiomyomas. Similarly, a previous report also showed that
68Ga-NEB PET/CT presented more clinically important information than did
99mTc-ASC lymphoscintigraphy in patients with lymphedema or chylous leakages [
14]. This might be due to the fact that
99mTc-ASC lymphoscintigraphy has an intrinsic disadvantage compared with
68Ga-NEB PET/CT. PET has greater intrinsic sensitivity compared to SPECT, and
68Ga-NEB PET has better spatial resolution than
99mTc-ASC lymphoscintigraphy. In addition,
68Ga-NEB PET/CT images are dynamic 3-dimensional whereas traditional
99mTc-ASC lymphoscintigraphy acquires only static 2-dimensional images.
68Ga-NEB PET/CT is also advantageous over
99mTc-ASC lymphoscintigraphy in shorter waiting and acquisition time.
Lymphatic system abnormality has always been considered as complications of LAM and is reported to be found in about 20% of LAM patients [
27,
28]. In our study, 70% (7/10) patients presented with extrapulmonary lymphatic manifestations on
68Ga-NEB PET/CT. However, the demonstration of the existence of pulmonary lymphatic changes with
68Ga-NEB PET/CT increases the proportion of cases with lymphatic involvement in our population to 100%. Based on this finding, we speculate that LAM patients who were diagnosed with only pulmonary cystic changes in the past might also have lymphatic involvement which conventional imaging methods failed to detect. Our finding of a high proportion of LAM cases with lymphatic involvement combined with the findings of histopathological studies suggest that lymphatic dysfunction may be a key mechanism in LAM pathogenesis [
19‐
22]. Elucidation of the role of lymphatic dysfunction in LAM may have the potential to develop new therapies targeting lymphatic circulation to inhibit the progression of LAM [
19]. Therefore, a great deal remains to be learned about lymphatic involvement in LAM, including its role in pathogenesis of the disease and its potential as a treatment target.
Several limitations of this study must be pointed out. First, the study is limited by the lack of histopathologic correlation of 68Ga-NEB PET/CT findings of pulmonary lymphatic changes. The second limitation is the small sample size of 10 patients with LAM. In future studies, we will collect more patients with LAM to further investigate the role of 68Ga-NEB PET/CT in assessing severity degree, treatment response, and predicting the prognosis of the disease. Thirdly, 68Ga-NEB PET/CT is able to visualize the pulmonary lymphatic abnormality and may have the potential in separating LAM from other cystic lung diseases such as emphysema, Langerhans cell histiocytosis, Sjögren syndrome with cystic changes in lung, and Birt-Hogg-Dubé syndrome. However, the current study did not examine the findings of 68Ga-NEB PET in other cystic lung diseases. In the future, studies investigating the 68Ga-NEB PET/CT findings of other cystic lung diseases were required to confirm this. In addition, we did not make correlations between VEGF-D level and the degree of lymphatic abnormality with 68Ga-NEB PET/CT in this study because VEGF-D data is not available in every patient. Besides, the sample size of 10 patients is too small, making it difficult to grade the severity of lymphatic abnormality with 68Ga-NEB PET/CT. In the future, we will collect more patients to grade the severity of lymphatic abnormality with 68Ga-NEB PET/CT, and to correlate VEGF-D level with 68Ga-NEB PET/CT findings.
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