Usefulness of 99mTc-ASC lymphoscintigraphy and SPECT/CT in the evaluation of rare lymphatic disorders: Gorham-Stout disease, lymphangioma, and lymphangioleiomyomatosis.

The purpose of this study was to investigate the role of Tc-antimony sulfide colloid (ASC) lymphoscintigraphy and single photon emission computed tomography/computed tomography (SPECT/CT) in the evaluation of rare lymphatic disorders, including Gorham--Stout disease (GSD), lymphangioma, and lymphangioleiomyomatosis (LAM).Nine patients suspected to have rare lymphatic disorders were included in this retrospective study. All patients underwent Tc-ASC lymphoscintigraphy and SPECT/CT to evaluate the lesions. The lymphoscintigraphy results were compared with the clinical and immunopathological findings.Tc-ASC lymphoscintigraphy and SPECT/CT could provide lymphatic draining and anatomical information for rare lymphatic disorders. Among the 9 patients, 3 were diagnosed with GSD (1 female, 2 males; aged 15-34 years, range 27.0 ± 10.4 years), 3 with lymphangioma (1 female, 2 males; aged 17-42 years, range 32.0 ± 13.2 years), and 3 patients were diagnosed with LAM (3 females; aged 33-50 years, range 43.7 ± 9.3 years]. GSD is characterized by multiple bone destruction, including spine, ribs, ilium, pubis, ischium, and femur. The tracer uptake of involved bones and soft tissue around bone is increased, accompanied by chylothorax, chylopericardium, and chylous leakage in abdominal and pelvic cavity. Lymphangiomas present as multiple cystic lesions with increased tracer uptake in the peripancreatic, retroperitoneal, and iliac areas, and in the abdominopelvic cavity. LAM presents as multiple thin-walled cysts in the bilateral lungs and multiple retroperitoneal enlarged lymph nodes with increased tracer uptake.Tc-ASC lymphoscintigraphy and SPECT/CT could comprehensively and specifically detect some rare lymphatic disorders, namely, GSD, lymphangioma, and LAM. This technique is useful for the evaluation of GSD, lymphangioma, and LAM.

Introduction

Gorham–Stout disease (GSD), lymphangioma, and lymphangioleiomyomatosis (LAM) are rare lymphatic disorders.[ GSD is characterized by massive osteolysis resulting from bone-replacing abnormal capillary proliferation early in the disease or fibrous hyperplasia in the later stage.[ Only about 300 cases of GSD have been reported in the literature.[ All bones could be affected, but the most common areas are the skull, shoulder girdle, pelvis, and extremities.[ The osteolytic lesions in GSD are related to the local lymphatic vessel proliferation.[ The distribution of lymphatics in GSD-affected bones is abnormal, whereas no such vessels are found in normal bones. Osteoclast activation and lymphangiogenesis are the necessary conditions for development of GSD.[ Lymphangiomas are congenital benign tumors of the lymphatic system.[ The exact etiology of lymphangiomas remains unknown, but they might be associated with congenital disorders in the embryological development of lymphatics, or may be caused by lymphatic obstruction secondary to lymphatic hemorrhage or inflammation.[ One characteristic of LAM is a multifocal nodular proliferation[ of immature smooth muscle and perivascular epithelioid cells (LAM cells),[ which could secrete vascular endothelial growth factor-D (VEGF-D) to promote lymphatic formation.

These 3 rare diseases are usually evaluated by traditional imaging examinations, including ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI).[ The role of lymphoscintigraphy, a nuclear medicine imaging method, is not fully recognized in the evaluation of these 3 lymphatic disorders due to their rarity. The procedure of lymphoscintigraphy is quite simple and safe, and only requires a subcutaneous injection of a small amount of a radiotracer. In the subcutaneous tissue, the radiotracer is taken up by the lymphatic vessels and lymphatic images are acquired by a gamma camera.[ As lymphoscintigraphy is a specific tool for lymphatic system imaging,[ we expected that 99mTc-antimony sulfide colloid (ASC) lymphoscintigraphy combined with single photon emission computed tomography/CT (SPECT/CT) might be able to provide comprehensive information of the 3 rare lymphatic disorders for the clinical physician. Accurate diagnosis and evaluation of lymphatic disorders are crucial for the therapeutic approach.[

Given the characteristics of lymphoscintigraphy and the pathological features of GSD, lymphangioma, and LAM, we investigated the role of 99mTc-ASC lymphoscintigraphy and SPECT/CT in the evaluation of these 3 rare lymphatic disorders.

Patients and methods

Ethical considerations

This retrospective study of existing patient data and images was approved by the institutional review board of Peking Union Medical College Hospital. The requirement for informed consent was waived.

Patients

Nine patients who were suspected to have rare lymphatic disorders and underwent 99mTc-ASC lymphoscintigraphy and SPECT/CT to evaluate the lesions from April 2015 to January 2020 were included in this retrospective study. The lymphoscintigraphy results were compared with the clinical and immunopathological findings.

GSD, lymphangioma, and LAM diagnosis

The histopathological diagnosis of GSD was based on extensive loss of bony matrix replaced by proliferation of thin-walled capillary-sized vascular channels, and at a later stage, by fibrous connective tissue.[ Dilated lymph vessels are the typical histopathological finding of lymphangioma, which is usually present as a cystic structure on imaging.[ According to the diagnosis guidelines, a definite diagnosis of LAM can be made based on the presence of cystic changes on high-resolution CT of the chest and any of the following confirmatory features: renal angiomyolipoma, chylous effusion, lymphangioleiomyoma, adenopathy, lymphatic vessel dilation, and either definite or probable tuberous sclerosis complex.[

99mTc-ASC lymphoscintigraphy

Lymphoscintigraphy was performed 1 hour after 99mTc-ASC was subcutaneously injected into the first and second interdigital spaces of both feet (0.5 mL, 37 MBq/foot). Images were acquired with a double-head gamma camera and a low-energy high-resolution parallel whole collimator in whole-body scanning mode with a 256 × 1024 matrix at a scan speed of 15 cm/min. SPECT/CT (Philips, Precedence 16P, the Netherlands) fusion images of the mainly affected area were obtained 2 hours after radiotracer injection. SPECT imaging was performed using a 128 × 128 matrix with a spacing of 3.0 mm, 32 projections over 360°, and 40 seconds per projection. A CT scan of the same anatomical region was obtained with 110 kV, 75 mAs, and pitch 1.3. Iterative reconstruction of the SPECT data was performed using an ordered-subset maximum-likelihood expectation-maximization algorithm; 3 iterations, 8 subsets, including resolution recovery.

Image interpretation

Visual methods were applied for image analysis. The images were analyzed by 2 experienced nuclear medicine physicians, who visually evaluated the lymphatic system, including the morphology and distribution.

Results

Patients’ characteristics

A total of 9 patients (7 females, 2 males; aged 15–50 years, mean age, 34.1 ± 12.1 years) were included. Among them, 3 patients were diagnosed with GSD (1 female, 2 males; mean age 27.0 ± 10.4 years, range 15–34 years), 3 were diagnosed with lymphangioma (1 female, 2 males; mean age 32.0 ± 13.2 years, range 17–42 years), and 3 were diagnosed with LAM (3 females; mean age 43.7 ± 9.3 years, range 33–50 years). The 3 rare lymphatic disorders involved multiple organs, including the lymphatics, bones, lungs, pleura, omentum, and subcutaneous soft tissues.

GSD

The clinical symptoms of these 3 patients included bone pain, dyspnea, abdominal distention, and limb swelling. The β-carboxy-terminal collagen crosslinks (β-CTX) level was elevated in 2 of 3 patients, whereas the serum albumin and total protein levels were normal in all 3 patients (Table 1). Lymphoscintigraphy and SPECT/CT demonstrated multiple 99mTc-ASC uptake sites in the skeletal system, including the spine, ribs, ilium, pubic bone, ischia, and femoral heads. The images also demonstrated tracer uptake in the surrounding tissues of the affected bones, including the pleurae, omentum, and subcutaneous soft tissue. In addition, pleural and pericardial effusions, abdominal and pelvic effusions, and lymphedema in the lower back, hip, and left lower limb were also observed by lymphoscintigraphy (Fig. 1).

Table 1

The imaging findings and clinical characters of Gorham–Stout disease.

Figure 1

Representative images of Gorham–Stout disease in patient 2. (A) Anterior image of lymphoscintigraphy obtained 1 h after 99mTc-ASC injection; (B) anterior image of lymphoscintigraphy obtained 3.5 h after 99mTc-ASC injection; (C–E) Axial SPECT, CT, and fusion images of the pelvis (bone window); (F–H) sagittal SPECT, CT, and fusion images of the pelvis (bone window); (I–K) axial SPECT, CT, and fusion images of the pelvis (soft-tissue window).

Lymphangioma

The clinical symptoms of patients suspected to have lymphangioma were abdominal distention, abdominal ache, weight loss, diarrhea, hematochezia, and weakness. The red blood cell count and hemoglobin level were decreased in 2 of 3 patients. The serum albumin and total protein levels were reduced in 1 of 3 patients (Table 2). Lymphoscintigraphy and SPECT/CT showed multiple clear-edged cystic masses with 99mTc-ASC uptake in the peripancreatic, retroperitoneal, and iliac areas, and in the abdominopelvic cavity. The imaging findings also revealed radiotracer uptake in the jejunoileal and colonic walls (Fig. 2).

Table 2

The imaging findings and clinical characters of lymphangioma.

Figure 2

Representative images of lymphangioma in patient 5. (A) Anterior image of lymphoscintigraphy obtained 1 h after 99mTc-ASC injection; (B–D) axial SPECT, CT, and fusion images of the pelvis; (E–G) axial SPECT, CT, and fusion images of the abdomen; (H–J) coronary SPECT, CT, and fusion images of the abdominopelvic region.

LAM

The clinical symptom of patients with LAM was dyspnea. The VEGF-D level was elevated in two patients; patient 3 did not undergo this examination. The forced expiratory volume in 1 second (FEV1) was <80% of the predicted and the FEV1/forced vital capacity (FVC) ratio was <70% in 2 of 3 patients (Table 3). In 2 of 3 patients, lymphoscintigraphy and SPECT/CT revealed multiple thin-walled cysts in the bilateral lungs with 99mTc-ASC uptake, which was more intense in the 2 lower lobes. In addition, the images showed enlarged lymph nodes in the retroperitoneum with intense 99mTc-ASC uptake (Fig. 3).

Table 3

The imaging findings and clinical characters of LAM.

Figure 3

Representative images of lymphangioleiomyomatosis in patient 8. (A) Anterior image of 99mTc-ASC lymphoscintigraphy after 1-h injection; (B–D) axial SPECT, CT, and fusion images of chest; (E–G) coronary SPECT, CT, and fusion images of chest; H-J, axial SPECT, CT, and fusion images of the abdomen.

Discussion

The evaluation of lymphatic disorders is difficult using CT and MRI, which only provide anatomical information, without a functional status. The lymphatic system imaging method, lymphoscintigraphy, should be specific for lymphatic disorders, particularly in rare diseases. In this study, we investigated the role of 99mTc-ASC lymphoscintigraphy and SPECT/CT in the evaluation of these rare diseases and found that this method enabled comprehensive evaluation of rare lymphatic disorders.

The mechanisms behind the osteolysis in GSD are not clear, but it is known that the osteolytic lesions in GSD are related to local lymphangioproliferation.[ The distribution of lymphatics in GSD-affected bones is abnormal, whereas no such vessels are found in normal bones. Accordingly, we expected that lymphoscintigraphy might have a potential to evaluate GSD. The diagnosis of GSD is mainly based on the clinical information and the histopathologic and radiographic findings.[ The commonly used radiological examinations for the evaluation of GSD are X-ray, ultrasound, CT, bone scan, and MRI.[ As lymphoscintigraphy was found to be helpful for the diagnosis of lymphedema and chylous effusion,[ and GSD is a lymphatic disorder, lymphoscintigraphy might play a role in the evaluation of GSD.

The clinical manifestations and complications of GSD depend on the invasion of the affected bones and surrounding tissues.[ When the ribs, thoracic vertebrae, or scapula are affected, chylothorax may be caused by the expansion and/or rupture of lymphatics into the chest or the invasion through the thoracic duct,[ as was seen in our patient 1.

β-CTX is a piece of collagen released into the blood after degradation in the process of bone remodeling. The increase of β-CTX content reflects the degree of bone absorption and the increase of bone loss, leading to the occurrence of osteoporosis and deformable osteopathy,[ such as GSD. β-CTX is a commonly used biomarker of osteoclastic bone resorption for the prediction of bone mass loss.[ In our study, the β-CTX level was elevated in 2 of 3 patients (2 of 3, 75%). The serum albumin and total protein levels were normal in all 3 patients, indicating that these patients in this study did not have protein loss.

99mTc-ASC lymphoscintigraphy combined with SPECT/CT might outperform the planar image of lymphoscintigraphy alone in the evaluation of GSD because SPECT/CT could supply the lymphatic draining and anatomical information for accurate and systematic evaluation.

Lymphangiomas, most commonly found in children, usually occur in the head, axillary regions, and the neck.[ Less than 1% of patients present with cystic lymphangiomas in the greater omentum, mesentery, and retroperitoneum.[ Lymphangiomas in the retroperitoneal and iliac regions are very rare.[ In our study, lymphangiomas were found in the peripancreatic, retroperitoneal, and iliac areas, and in the abdominopelvic cavity. In addition, we also found lymphangioma in the jejunoileal and colonic walls. The clinical symptoms of lymphangioma were reported to be abdominal distention, abdominal pain, diarrhea, gastrointestinal bleeding, and hypoproteinemia.[

Imaging studies are important for diagnosing lymphangioma.[ CT or MRI can localize the lesion and reveal its cystic structure, suggesting the possibility of lymphangioma,[ but nontumorous cystic lesions, including abscesses and tumorous cystic lesions such as mesothelioma, should be differentiated.[ At CT or MRI, lymphangiomas and other cystic lesions are often difficult to differentiate. Radionuclide studies may be useful to further characterize tumors and investigate tumor-related pathophysiology.[ In particular, lymphoscintigraphy is useful to diagnose lymphangioma and demonstrate the communication between the tumor and the lymphatic system.[ Accurate diagnosis and evaluation of lymphangioma are important for the surgical treatment and prognosis because recurrence rates after incomplete resection are higher than those after complete resection (35–64% vs 17–24%).[

In this study, all 3 patients were diagnosed with LAM according to the 2016 American Thoracic Society Guidelines.[ In these patients, dyspnea, pneumothorax, and hemoptysis are common manifestations, while chylothorax, chylous ascites, and lymphangiomyoma are also frequently seen.[ As lymphoscintigraphy was found to be helpful for the evaluation of lymphatic disorders,[ we investigated the role of 99mTc-ASC lymphoscintigraphy and SPECT/CT in the evaluation of LAM.

The rate of positive LAM findings on 99mTc-ASC lymphoscintigraphy and SPECT/CT was 75%. As a functional imaging method, lymphoscintigraphy could reveal the pulmonary and extrapulmonary LAM lesions and might play an alternative role in the diagnosis and evaluation of LAM.

As a whole-body imaging method,99mTc-ASC lymphoscintigraphy could comprehensively evaluate the lymphatic drainage function, particularly in rare lymphatic disorders whose diagnosis and evaluation on CT and MRI is challenging. The combination of 99mTc-ASC lymphoscintigraphy and SPECT could accurately reveal the sites of lymphatic malformation, which is important for the treatment schedule. In addition, this study adds to the clinical cognition of rare lymphatic disorders and the role of lymphoscintigraphy, which may be helpful for clinical physicians to diagnose and evaluate those diseases.

In this study, we found that the VEGF-D level was elevated in two patients (2/2, 100%; this test was not performed on patient 9). The promoting lymphangiogenic growth factor, VEGF-D, has been proposed as a potential diagnostic marker for LAM.[ Serum VEGF-D level is elevated (> 800 pg/mL) in approximately 70% of patients; however, a negative serum VEGF-D result does not exclude a diagnosis of LAM.[ The FEV1 was <80% and FEV1/FVC ratio was <70% in two of three patients (patients 7 and 9), indicating that these patients had obstructive ventilatory defects.[

The main limitation of this study is the limited sample size of patients with GSD, lymphangioma, and LAM, which greatly affects the analysis of the results. Therefore, in this manuscript, we mainly describe the performance of the disease on SPECT lymphoscintigraphy and focus on the characteristics of the images of these unusual lymphatic disorders. More cases should be included in further studies to investigate the role of 99mTc-ASC lymphoscintigraphy and SPECT/CT in assessing the three rare lymphatic disorders systematically and comprehensively.

Conclusion

99mTc-ASC lymphoscintigraphy and SPECT/CT could comprehensively and specifically evaluate rare lymphatic disorders, namely, GSD, lymphangioma, and LAM. This technique is useful for the evaluation of GSD, lymphangioma, and LAM.

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Author contributions

Data curation: Wenshuai Xu.

Project administration: Fang Li, Wuying Cheng.

Resources: Kai-Feng Xu, Wuying Cheng.

Visualization: hongli jing.

Writing – original draft: Guozhu Hou, Yuanyuan Jiang.

Writing – review & editing: Libo Chen, Wuying Cheng.