Primary extremity lymphedema is a debilitating disease with a reported incidence of 1–3 in every 10,000 births, and it may present with concomitant vascular lesions or retroperitoneal lymphangiomatosis with chylous ascites.
The diagnosis of primary extremity lymphedema includes history, physical examination, lymphoscintigraphy, and indocyanine green lymphography. Doppler ultrasound and computed tomography angiography are the key evaluation tools for concomitant vascular lesions. Magnetic resonance imaging and single photon emission computed tomography are required for the diagnosis of retroperitoneal lymphangiomatosis.
Microsurgical procedures, including lymphovenous anastomosis and vascularized lymph node transfer, have been shown to provide functional improvements in primary extremity lymphedema. Most patients with primary extremity lymphedema require vascularized lymph node transfer due to severe and prolonged symptoms or total obstruction on lymphoscintigraphy.
Vascular stenting is indicated and effective for proximal venous or arterial occlusion, which is recommended to be performed 6 months before lymphedema microsurgery for primary extremity lymphedema.
Chylovenous bypass is effective for solving the problem of retroperitoneal lymphangiomatosis and can be performed at the time of lymphedema microsurgery if diagnosis is confirmed along with primary extremity lymphedema.
Primary extremity lymphedema is a debilitating disease with a reported incidence of approximately 1–3 out of every 10,000 births and with a female to male ratio of 3.5:1. It can be categorized according to the age of onset: congenital (onset at birth), praecox (after birth and before 35 years of age), and tarda (after the age of 35). Specific gene mutations have been identified in primary lymphedema patients, including mutations of VEGFR3 (Milroy’s disease), PIEZO1, EPHB4, CCBE1 (Hennekam’s syndrome), PIK3/AKT/mTOR pathway (PIK3CA-related overgrowth spectrum, SOX18 (hypotrichosis-telangiectasia-lymphedema), FOXC2 (lymphedema distichiasis), and KIF11 (microcephaly-chorioretinopathy-lymphedema-mental retardation). In addition to the clinical history and physical examination needed for diagnosis, recent advances in the use of Tc-99 lymphoscintigraphy and indocyanine green (ICG) lymphography have markedly improved the diagnosis of primary extremity lymphedema. While the definite surgical treatment for patients with primary extremity lymphedema has yet to be proven, studies have shown that microsurgical procedures such as lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) can provide effective treatment. However, there is little to be found in the literature concerning the long-term prognosis of primary extremity lymphedema.
Concomitant vascular and other lymphatic lesions such as venous thrombosis, vascular malformations, arterial occlusions, and retroperitoneal lymphangiomatosis causing chylous ascites may contribute to primary extremity lymphedema and even make primary extremity lymphedema more severe. The incidence of vascular and other lymphatic diseases occurring in primary extremity lymphedema patients has seldom been reported. These other diseases are frequently neglected, and the diagnosis is also much more difficult.
In this chapter, the authors highlight their clinical experience as well as review the relevant literature to provide recommendations for the diagnosis and treatment of primary extremity lymphedema with concomitant vascular and lymphatic diseases.
Previous reports show that 20–30% of patients with chronic venous diseases also have associated lymphatic dysfunction, possibly due to cellulitis or overload of the lymphatic system. Therefore, a potential synergistic effect might exist between venous obstruction and lymphatic dysfunction. Szuba et al. reported that 4.6% of patients with extremity lymphedema had concomitant venous obstruction. Sachanandani et al. reported that 15 of 95 (15.8%) patients with extremity lymphedema had concomitant vascular lesions.
Lymphangiomatosis is a rare condition with an unclear incidence where hyperproliferation of lymphatic vasculature causes lymphangiomas and affects soft tissue and viscera, and osseous involvement is sometimes present. The major complications of lymphangiomatosis include chylothorax, chylous pericardial effusion, and chylous ascites. In particular, retroperitoneal lymphangiomatosis may present with chylous ascites as well as concomitant lower limb lymphedema. Previously, the care for retroperitoneal lymphangiomatosis involved symptomatic care with thoracocentesis, pleurodesis, or paracentesis, combined with lymphedema therapy. In one study, 6 of 44 (13.6%) primary extremity lymphedema patients were found to have retroperitoneal lymphangiomatosis.
Considering the relatively high prevalence of concomitant vascular and lymphatic lesions in patients with primary extremity lymphedema and the synergistic severity of lymphedema, early detection and timely intervention of the concomitant diseases to counteract the disease progression are warranted.
Currently, there are no widely recognized guidelines for the treatment of patients with primary extremity lymphedema. However, the basic principles of diagnosis and the treatments for secondary extremity lymphedema should be applied to primary extremity lymphedema. The major differences between primary and second extremity lymphedema include an earlier onset of symptoms, a longer symptom duration, more intense severity, and the possibility of comorbidities of other vascular or lymphatic diseases.
Clinical evidence supports that these patients can benefit from microsurgical procedures such as LVA and VLNT. Comparing these two techniques, Cheng et al. performed both procedures on 17 primary lymphedema patients totaling 19 lymphedematous extremities. Patients showing patent lymphatic ducts on ICG lymphography were indicated for LVA, while those without patent ducts underwent VLNT. The study showed that VLNT could provide greater functional improvement than LVA, including a decrease in limb circumference and a decrease in body weight. In another study by Cheng MH et al. (online ahead of print), microsurgical treatment was shown to provide benefits to pediatric patients with congenital extremity lymphedema.
Concomitant Vascular Lesions
The screening modalities for vascular lesions with secondary extremity lymphedema include Doppler ultrasound, contrast venography, intravascular ultrasound (88% sensitivity for detecting venous obstruction with greater than 50% area stenosis), and computed tomography angiography (CTA). Traditional angiography, which can be both diagnostic and therapeutic, is suggested in cases where the result of CTA is equivalent.
For the diagnosis of retroperitoneal lymphangiomatosis, the methods that are currently being used include direct lymphangiography followed by computed tomography (CT) and magnetic resonance imaging (MRI). Chen et al. performed MRI in patients with primary extremity lymphedema who also presented with abdominal symptoms and/or ascites in order to view extravasation of chyle into the peritoneal cavity. If the examination was positive, a single photon emission CT (SPECT) scan was then performed to visualize the retroperitoneal lymphatic malformation. Seven patients underwent exploratory laparotomy under the suspicion of retroperitoneal lymphangiomatosis, and six were positive, yielding a specificity of 85.7% when both MRI and SPECT were utilized ( Fig. 5.1 ).
Selection of the Lymphedema Microsurgery Technique
For patients whose extremity lymphedema is of Cheng’s Lymphedema Grade II–IV and who present with total obstruction on Tc-99 lymphoscintigraphy or a lack of patent lymphatic ducts on ICG lymphography, VLNT is indicated. For those who have Cheng’s Lymphedema Grade I–II, partial obstruction on Tc-99 lymphoscintigraphy, and patent lymphatic ducts on ICG, LVA is preferred. Cheng et al. found that 84.6% of congenital extremity lymphedema patients required VLNT. Due to the initial severity of primary extremity lymphedema combined with delayed diagnosis and treatment, VLNT may be required in most cases of primary extremity lymphedema ( Fig. 5.2 ).
Timing of Vascular Intervention
It was shown that patients who received interventions for their vascular diseases prior to VLNT had better functional outcomes at the 12-month follow-up compared to those who received vascular interventions concurrently or after VLNT for extremity lymphedema, but no significant difference was found at the final follow-up. However, the compressive environment caused by both lymphedema and venous hypertension may have increased the risk of venous thrombosis after VLNT. Hence, the authors recommend that vascular interventions should be performed prior to VLNT, with a 6-month waiting period afterward to allow the venous system to equilibrate.
Lymphedema microsurgery, including VLNT and LVA, may be performed as described in other chapters. The authors prefer to perform side-to-end LVA for Cheng’s Lymphedema Grade I–II primary extremity lymphedema and submental VLNT for Grade II–IV patients.
Treatment for Concomitant Vascular Lesions
Interventions are required to treat vascular lesions according to the nature and severity of the individual lesion. These interventions may include an external release of fibrotic tissue, vascular stenting, balloon angioplasty, and thrombectomy. Most vascular lesions may be managed by collaboration with vascular surgeons or interventional radiologists.
Intra-abdominal Chylovenous Bypass
There is limited evidence for medical treatments such as bisphosphonate, sirolimus, interferon, and radiotherapy for retroperitoneal lymphangiomatosis. The surgical treatments that have been explored thus far include repair and ligation of ectatic lymphatic channels, sclerotherapy, chylovenous anastomoses, exeresis, CO 2 laser, and chylovenous/lymphovenous shunts. Campisi et al.’s lymphovenous shunting technique was varied and included direct lymphatic repair, chylous channel/cyst-to-venous shunt anastomosis, and lymphatic-to-venous anastomosis with vein grafts.
In Chen et al.’s study conducted between 2012 and 2018, intra-abdominal chylovenous bypass (CVB) with VLNT was performed for patients who had retroperitoneal lymphangiomatosis with chylous ascites and concomitant primary lower extremity lymphedema. In the majority of cases, submental VLNT was performed prior to CVB to relieve extremity lymphedema. VLNT was the operation of choice since these patients with associated retroperitoneal lymphangiomatosis usually had longer symptoms and severe lymphatic obstruction. The donor sites were selected from either the omental or submental basins.
CVB was first described by Chen et al. in 2019 to bypass the intra-abdominal chylous ascites into the venous system. During exploratory laparotomy, the chyle leakage caused by the malformation of lymphatics was identified from the visualization of focal milky exudate by exploration of the retroperitoneum and then confirmed under the microscope. Typically, the location was found to be between the level of the umbilicus and that of the anterior superior iliac spine, around the ureter and internal iliac artery. Bipolar cautery was used to create a hole 4 mm in diameter on the surface of the lymphangiomatosis soft tissue to provide a controlled outlet for chyle. For the recipient vein, either the ovarian vein or branches of the internal iliac vein was utilized for the drainage of chyle. The distal end of the recipient vein was then anastomosed to the lymphangiomatosis outlet in a side-to-end fashion using 8–12 interrupted stitches with 9-0 nylon. The patency was then confirmed with ICG injection at the distal site of lymphangiomatosis ( Fig. 5.3 ).