Microsurgery guided by sequential preoperative lymphography using 68Ga-NEB PET and MRI in patients with lower-limb lymphedema

Abstract

Objective: The popularity of contemporary microsurgical techniques in treatment of lower-limb lymphedema calls for better visualization of the lymphatic system, both preoperatively and intra-operatively. The aim of this prospective study was to investigate the feasibility of a novel combination of ⁶⁸Ga-NEB positron emission tomography (PET) with magnetic resonance lymphography (MRL) in evaluating lymphedema and guiding surgical intervention.

Methods: A total of 11 patients (F 9, M 2, age range 29-69 y) with lower-limb lymphedema classified into stage I to III were recruited. PET acquisition was performed at 30, 60 and 90 min after subcutaneous injection of the albumin-binding radiotracer ⁶⁸Ga-NEB into the bilateral first web spaces of the feet. All the patients were also subjected to ^99mTc-sulfur colloid (SC) lymphoscintigraphy for comparison. Gd-DTPA-enhanced magnetic resonance imaging (MRI) was performed using sequences specialized for lymphatic vessel scans. All the patients underwent surgical interventions within a week. The surgical approach includes the use of a linear marker for edema localization and indocyanine green (ICG) lymphography with a near-infrared surgical navigation system intra-operatively.

Results: Lymph transport in lymphatic channels was clearly observed by visualization of ⁶⁸Ga-NEB activity in the lymphatic vessels and within lymph nodes for all 11 patients as well as the visualization of the edema section plane with dermal backflow (DB), abnormally increased and disconnected uptake along the lymphatic channels. Preoperative ⁶⁸Ga-NEB PET combined with MRL provides advantageous three-dimensional images, higher temporal resolution, significantly shorter time lapse before image acquisition after tracer injection and more accurate pathological lymphatic vessel distribution than ^99mTc-SC lymphoscintigraphy combined with MRI.

Conclusion: This study documented an effective imaging pattern to combine ⁶⁸Ga-NEB PET and MRL in patients with lower-limb lymphedema. This strategy demonstrated significant advantage over ^99mTc-SC lymphoscintigraphy/MRL in the evaluation of lymphedema severity, staging and pathological location of lymph vessels to make an individualized treatment plan. Dual ⁶⁸Ga-NEB PET/MRL is thus recommended before the operation for staging and therapy planning.

Keywords: 68Ga-NEB; Evans blue dye; ICG; Lymphangiography; Lymphedema; PET-MR.

Figure 1

Imaging procedures of ⁶⁸Ga-NEB PET/MR/ICG fluorescence lymphangiography. Albumin-binding radiotracer ⁶⁸Ga-NEB was injected subcutaneously into the bilateral first web spaces of the feet. Patients were requested to walk for 30 min and then PET image acquisition was performed. (A) Structure of ⁶⁸Ga-NEB. (B) Representative maximum intensity projection of ⁶⁸Ga-NEB PET with high signal intensity line of the lymphatic vessels acquired at 60 min after tracer administration. (C) Injection site of ⁶⁸Ga-NEB to a patient with lymphedema. (D) A representative contrast enhanced 3D MR image of lymphatic vessels after subcutaneous injection of Gd-DTPA. (E) Structure of ICG. (F) Real time ICG lymphography acquired intraoperatively. (G) The fluorescence camera used for ICG imaging.

Figure 2

Imaging guided surgery in a patient with stage I lymphedema. (A) ^99mTc-SC lymphoscintigraphy with anterior and posterior views showed dermal backflow from left calve to thigh and lymph node accumulation defect of the left side. The images were acquired at 6 h after tracer administration; (B) T₁-weighted MR lymphangiography using 3-dimensional gradient recalled echo (LAVA) (left) and fast spin echo (FSE) (middle) showed twisted, compensatory and discontinuous lymphatic channels of left medial calf (arrows). T₁-weighted with LAVA MIP reconstruction (right) showed multi-strip expansion and compensatory channels of left medial calf (arrows). (C–G) ⁶⁸Ga-NEB PET lymphangiography acquired at 60 min after tracer administration showed slight dermal backflow of the left lower-limb (C and G), lymph node accumulation defect at affected side (C) including left inguinal region (D), abnormal lymphatic channels at left lower medial calve (F) and potential anastomosis pathway inside of medial calf (E). (H) Intraoperative ICG fluorescence lymphangiography provides real-time delineation of subdermal lymphatics inside of medial calf. (I–K) Personalized surgical plan and lymphatic venous anastomosis (LVA) were performed with end-to-end lymphatic channel and suitable sized adjacent subcutaneous venule anastomosis. A length of dilated channel dissected was further confirmed as the lymphatic vessel (I) with pathological HE staining (K).

Figure 3

Imaging guided surgery in a patient with stage II lower-limb lymphedema. (A) ^99mTc-SC lymphoscintigraphy showed dermal backflow of the left lower-limb, asymmetrical distribution of bilateral lymph nodes and accumulation defect on the left side. (B–C) MR lymphangiography showed dilated and discontinuous lymphatic channels of the left medial calf (arrows). (D–H) 68Ga-NEB PET lymphangiography (60 min after tracer administration) represented “Honeycomb Pattern” with dilated dermal lymphatics, discontinuous lymphatic channels and compensatory vessels and lymph lakes of the left lower-limb (D), as well as different levels of dermal backflow (E and F) and lymph node accumulation defect on the affected left side (G and H). (I–L) A typical workflow of imaging guided surgery planning using preoperative ⁶⁸Ga-NEB PET (I) and MRL (J) to discriminate the location of the lymphatic channels (K) for lymphatic venous anastomosis (L).

Figure 4

Imaging guided surgery in a patient with stage III lymphedema. (A) ^99mTc-SC lymphoscintigraphy (6h post injection) showed inguinal lymph node accumulation defect on the left side and dermal backflow of the left lower-limb. (B) MR lymphangiography showed increased subcutaneous thickness and diffuse fibrosis of the left lower-limb, a length of dilated and tortuous deep-seated lymph vessel of the affected medial calve. (C–H) ⁶⁸Ga-NEB PET lymphangiography (60 min post injection) presented large and diffuse dermal backflow of the lower-limb (C and D), lymph node accumulation defect on the left inguinal region and a length of dilated and tortuous lymphatic channels (E and F) of the affected medial calve. (I) Intraoperative ICG lymphangiography was unable to delineate lymphatic vessels due to limited penetration depth of optical Imaging and overall overgrowth of adipose tissue in stage III lymphedema.