Complex Lymphatic Anomalies: Report on a Patient Registry Using the Latest Diagnostic Guidelines.

Background: Generalized lymphatic anomaly (GLA), Gorham-Stout disease (GSD), kaposiform lymphangiomatosis (KLA), and central conducting lymphatic anomaly (CCLA) are rare, multisystem lymphatic disorders, referred to as complex lymphatic anomalies (CLAs). Their etiology remains poorly understood; however, somatic activating mutations have recently been discovered, and the results of targeted treatments are promising. This study aimed to elaborate on the phenotypic description of CLA. Methods: Thirty-six consecutive patients were recruited for the "GLA/GSD Registry" of the University Hospital of Freiburg, Germany (2015-2021). Clinical data were prospectively collected provided that a signed informed consent form was obtained. The latest proposed diagnostic guidelines were retrospectively applied. Results: Thirty-two patients (38% males) were included in the study; 15 GLA, 10 GSD, 3 KLA, and 4 CCLA patients were identified. Eighty-four percent already had symptoms by the age of 15 years. Osteolysis and periosseous soft-tissue infiltration were associated with GSD (p < 0.001 and p = 0.011, respectively), ascites and protein-losing enteropathy with CCLA (p = 0.007 and p = 0.004, respectively), and consumption coagulopathy with KLA (p = 0.006). No statistically significant differences were found in organ involvement, distribution of osteolytic lesions, number of affected bones and fractures. Twenty-five patients had complications; one patient with GLA died despite multimodal treatment. Spontaneous regression was seen in one patient with untreated KLA. Conclusions: CLA are rare, and their overlapping clinical presentations make differential diagnosis difficult. The characterization of our case series contributes to the phenotypic description and differentiation of these four clinical entities. A further understanding of their pathogenesis is crucial for evaluating targeted therapies and optimizing medical care.

An Integrative Therapeutic Concept for Surgical Treatment of Severe Cases of Lymphedema of the Lower Extremity.

BACKGROUND: Lymphedema results from insufficient lymphatic drainage and typically affects the extremities. Recent studies revealed obesity as another cause of extremity lymphedema. Conservative treatment of patients with elephantiastic lymphedema of the lower extremity is limited and often inadequate. Resecting surgery plays an important role in these cases. Here, we investigated the effects of an integrated therapy concept on outcome and complication rates. METHODS: We retrospectively analyzed the clinical outcome of 26 patients with elephantiastic lymphedema of the lower limb who underwent a complex decongestive physical therapy (CDP) perioperatively and reduction surgery in our clinic between 1998 and 2011. We subsequently compared these patients (group A) with a control group of 30 patients (group B) who received medial thigh lift due to post-bariatric or aesthetic issues between 2011 and 2013. The incidence of complications, reoperations, blood transfusion, and duration of hospital stay was analyzed. All patients in group A received CDP perioperatively in a specialized lymphological clinic. RESULTS: Both groups are comparable in terms of age and sex. Patients significantly differ in terms of BMI (p < 0.001). Thirty-six reductive procedures were performed in group A and 30 in group B. We did not see any significant difference in the incidence of complications (p = 1.000) and the rate of postoperative blood transfusions (p = 0.116). CONCLUSIONS: We were able to show that an integrative concept including surgery is a good additional option for the treatment of severe cases of lymphedema in appropriate candidates. Furthermore, an adequate perioperative conservative setting helps to minimize possible complications.

An integrated therapy concept for reduction of postoperative complications after resection of a panniculus morbidus.

BACKGROUND: Panniculus morbidus is characterized by an edematous, painful hanging abdominal mass, due to laxity and redundancy of the abdominal skin in morbid obesity, particularly after massive weight loss. Panniculectomy, by wedge resection, is a salvage procedure with high satisfaction rates though associated with high complication rates. Here we investigated the effects of perioperative complex decongestive physical therapy (CDP) on outcome and complication rates. METHODS: We retrospectively analyzed the clinical course and outcome of 24 patients receiving panniculectomy between 1998 and 2009 in our department of plastic surgery. Sixteen patients received perioperative CDP, and eight patients did not receive any form of decongestive treatment. We analyzed the incidence of complications, reoperation, blood transfusions, and length of hospital stay based on chart reviews. Complications were categorized as minor or major according to the necessity of readmission or reoperation. CDP was performed for 4-6 weeks preoperatively and 2 weeks postoperatively. RESULTS: The incidence of major complications (p = 0.001), the rate of postoperative blood transfusions (p = 0.028), wound healing disorders (p = 0.021), and the incidence for complications (p = 0.001), whether minor or major, were significantly reduced in the CDP group. In summary, 12 of 16 patients within the CDP group had an uneventful course, whereas all non-CDP patients had at least one complication. CONCLUSIONS: Adequate perioperative CDP treatment in a lymphological clinic may reduce the rate of early postoperative complications after resection of panniculus morbidus.

Assessment of the lymphatic system in patients with diffuse lymphangiomatosis by magnetic resonance imaging.

OBJECTIVE: To assess the lymphatic system in patients with diffuse lymphangiomatosis by magnetic resonance imaging. MATERIALS AND METHODS: 15 patients with diffuse lymphangiomatosis were examined by magnetic resonance imaging. Three locations were examined: first, the lower leg and foot region; second, the upper leg and the knee region; and third, the pelvic with retroperitoneal and abdominal region. For magnetic resonance lymphangiography a T1-weighted 3D spoiled gradient-echo and a T2-weighted 3D-TSE sequence was used. RESULTS: The size of the genital lymphangiomas, which were revealed in all patients, varied between 5 and 83 mm. In 47% of the patients lymphangiomas were detected at the level of the lower legs, and in 87% of the patients at the level of the upper leg and retroperitoneum. Furthermore, lymphangiomas were seen in the inguinal and pelvic region in 100% and intraabdominally in 40% of the patients. The lymphangiomas extended into the abdominal wall in 93% of the examined patients. A chylous pleural effusion was revealed in 20% and a chylous ascites in 13% of patients. 93% of patients suffered due to the diffuse lymphangiomatous pathologies from a lymphedema of the lower extremities, while a generalized lymphedema of the trunk was found in 87% of the patients. CONCLUSION: Magnetic resonance imaging is a safe and accurate minimal-invasive imaging modality for the evaluation of the lymphatic system in patients with diffuse lymphangiomatosis. Since the localization and extension of the lymphangiomas are important prognostic factors, it is crucial to perform a safe radiologic evaluation with a high resolution for the patient's therapeutic planning.

Diffuse lymphangiomatosis with genital involvement--evaluation with magnetic resonance lymphangiography.

OBJECTIVE: To assess, for the first time, the morphology of the lymphatic system in patients with diffuse lymphangiomatosis and genital involvement by magnetic resonance lymphangiography (MRL). MATERIALS AND METHODS: Ten patients with diffuse lymphangiomatosis and genital involvement were examined by MRL. Three locations were examined: first, the lower leg and foot region; second, the upper leg and the knee region; and third, the pelvic with retroperitoneal region. MR imaging was performed with a 1.5-T system equipped with high-performance gradients. For MRL, a T1-weighted 3D-spoiled gradient-echo and a T2-weighted 3D-TSE sequence were used. RESULTS: The size of the genital lymphangiomas, which were revealed in all patients, varied between 6 and 85 mm. In 60% of the patients, lymphangiomas were additionally detected at the level of the lower legs, and in 70% patients at the level of the upper leg. Furthermore, lymphangiomas were seen in the inguinal and retroperitoneal regions in 80%, and in the pelvic region and anterior abdominal wall in 90% of the patients examined. The genital lymphangiomas feeding lymphatic vessels were detected in 80% of the patients in the anterior abdominal wall and in 90% of the patients in the inguinal and pelvic regions; 90% of the patients suffered consecutively from a lymphedema of the lower extremities. All patients suffered from recurrent infections in the genital region; 80% of the patients repeatedly experienced genital lymphorrhea due to lympho-cutaneous fistulas and lymphcysts. CONCLUSION: MRL is a safe and accurate minimal-invasive imaging modality for the evaluation of the lymphatic circulation in patients with diffuse lymphangiomatosis and genital involvement. Because the site and extent of the lymphangiomas with their feeding lymphatic vessels are important prognostic factors, performing radiologic evaluation with a high resolution is crucial for the therapeutic planning of patients.

MR imaging of the lymphatic system in patients with lipedema and lipo-lymphedema.

OBJECTIVE: To assess for the first time the morphology of the lymphatic system in patients with lipedema and lipo-lymphedema of the lower extremities by MR lymphangiography. MATERIALS AND METHODS: 26 lower extremities in 13 consecutive patients (5 lipedema, 8 lipo-lymphedema) were examined by MR lymphangiography. 18 mL of gadoteridol and 1 mL of mepivacainhydrochloride 1% were subdivided into 10 portions and injected intracutaneously in the forefoot. MR imaging was performed with a 1.5-T system equipped with high-performance gradients. For MR lymphangiography, a 3D-spoiled gradient-echo sequence was used. For evaluation of the lymphedema a heavily T2-weighted 3D-TSE sequence was performed. RESULTS: In all 16 lower extremities (100%) with lipo-lymphedema, high signal intensity areas in the epifascial region could be detected on the 3D-TSE sequence. In the 16 examined lower extremities with lipo-lymphedema, 8 lower legs and 3 upper legs demonstrated enlarged lymphatic vessels up to a diameter of 3 mm. In two lower legs with lipo-lymphedema, an area of dermal back-flow was seen, indicating lymphatic outflow obstruction. In the 10 examined lower extremities with clinically pure lipedema, 4 lower legs and 2 upper legs demonstrated enlarged lymphatic vessels up to a diameter of 2 mm, indicating a subclinical status of lymphedema. In all examined extremities, the inguinal lymph nodes demonstrated a contrast material enhancement in the first image acquisition 15 min after injection. CONCLUSION: MR lymphangiography is a safe and accurate minimal-invasive imaging modality for the evaluation of the lymphatic circulation in patients with lipedema and lipo-lymphedema of the lower extremities. If the extent of lymphatic involvement is unclear at the initial clinical examination or requires a better definition for optimal therapeutic planning, MR lymphangiography is able to identify the anatomic and physiological derangements and to establish an objective baseline.

Posttraumatic edema of the lower extremities: evaluation of the lymphatic vessels with magnetic resonance lymphangiography.

OBJECTIVE: To assess for the first time the morphology of the lymphatic system in patients with posttraumatic edema of the lower extremities by magnetic resonance (MR) imaging using the interstitial lymphangiography technique MATERIALS AND METHODS: Six patients with posttraumatic edema in eight of their 12 lower extremities were examined by MR lymphangiography. Eighteen mL of gadoteridol and one mL of mepivacainhydrochloride 1% were subdivided into 10 portions and injected intracutaneously. MR imaging was performed with a 1.5-T system equipped with high-performance gradients. For MR lymphangiography, a 3D-spoiled gradient-echo sequence was used. RESULTS: In five of the eight (63%) traumatized lower extremities, enlarged lymphatic vessels were detected, with the largest diameter measuring 5 mm. Additionally, a fast lymphatic outflow was observed in seven of the eight (88%) traumatized legs with enhancement of the inguinal lymph nodes already in the first image acquisition 15 minutes after contrast material injection. In two of the eight (25%) traumatized lower extremities, an extensive network of collateral lymphatic vessels was detected at the level of the calf. In both extremities, lymphatic collateralization involved not only the epifascial but also the subfascial lymphatic system. In one patient, who sustained a trauma of the left lower leg with tibial fracture, a small aneurysmatic widening of 7 mm could be detected at the middle level of the calf. CONCLUSION: MR lymphangiography is a safe and accurate minimal-invasive imaging modality for the evaluation of the lymphatic circulation in patients with posttraumatic edema of the lower extremities. If the extent of lymphatic damage is unclear at the initial clinical examination or requires a better definition for optimal therapeutic planning, MR lymphangiography is able to identify the anatomic and physiological derangements and to establish an objective baseline.

HGF and MET mutations in primary and secondary lymphedema.

BACKGROUND: Lymphedema is the abnormal accumulation of protein-rich fluid in the interstitial space. Primary lymphedema is a rare genetic condition with both autosomal dominant and autosomal recessive modes of inheritance. Three genes, FLT4 (VEGFR3), FOXC2, and SOX18 cause varying forms of primary lymphedema. In industrialized countries, secondary lymphedema is usually associated with cancer therapy and/or trauma. Recent observations suggested that hepatocyte growth factor/high affinity hepatocyte growth factor receptor (HGF/MET) were new candidate lymphedema genes. METHODS AND RESULTS: The coding exons and flanking regions of HGF and MET were directly sequenced in 145 lymphedema probands, 59 unrelated women with secondary lymphedema following treatment for breast cancer, 21 individual patients with lymphedema and intestinal lymphangiectasia, and at least 159 unrelated ethnic matched control individuals. Mutations leading to truncation or missense changes in evolutionarily conserved residues of HGF and MET were identified. These mutations were not polymorphic in control individuals. CONCLUSIONS: The identification of HGF/MET mutations in primary lymphedema, lymphedema/lymphangiectasia, and breast cancer-associated secondary lymphedema suggests that the HGF/MET pathway is causal or alters susceptibility for a broad range of lymphedema phenotypes. The HGF/MET pathway provides a new target for the prevention and/or treatment of lymphedema.

MR lymphangiography for the assessment of the lymphatic system in patients undergoing microsurgical reconstructions of lymphatic vessels.

OBJECTIVE: To assess the morphology of the lymphatic system pre- and postoperatively in patients undergoing microsurgical reconstructions of the lymphatic vessels. MATERIALS AND METHODS: 8 lower extremities in 4 consecutive patients with secondary unilateral lymphedema of the lower extremities were examined by MR lymphangiography. 18 mL of gadoteridol and 1 mL of mepivacainhydrochloride 1% were subdivided into 10 portions and injected intracutaneously into the dorsal aspect of each foot at the region of the four interdigital webs and medial to the first proximal phalanx. MR imaging was performed with a 1.5-T system equipped with high-performance gradients. For MR lymphangiography a 3D-spoiled gradient-echo sequence was used. For evaluation of the lymphedema a heavily T2-weighted 3D-TSE sequence was performed. RESULTS: In 2 patients the 3D-TSE sequence demonstrated a decrease of the epifascial lymphedema in the postoperative acquisitions, whereby MR lymphangiography displayed an improvement of dermal-back areas and collateral lymphatic vessels. In one patient the epifascial lymphedema of the lower extremity decreased, whereas the diameter of the lymphatic vessels showed a constant diameter of 2 mm. In one patient with a lymphocutaneous fistula at the level of the right groin, the feeding lymphatic vessels and contrast media extravasation could clearly be visualized. The 3D-TSE sequence demonstrated an epi- as well as subfascial lymphedema of the right leg. CONCLUSION: MR lymphangiography is a safe and accurate diagnostic imaging method for the pre- and postoperative evaluation of the lymphatic circulation in patients undergoing microlymphatic surgery. Due to the minimal-invasiveness and lack of radiation, diagnostic follow-up MR lymphangiography examinations can be performed routinely and with no risk for the patient.

Interstitial MR lymphangiography - a diagnostic imaging method for the evaluation of patients with clinically advanced stages of lymphedema.

BACKGROUND: To assess the feasibility of interstitial magnetic resonance lymphangiography with intracutaneous injection of a commercially available, non-ionic, extracellular paramagnetic contrast agent, to visualize lymphatic vessels in patients with clinically advanced stages of primary lymphedema. METHODS: Sixteen lower extremities in 8 patients with clinically advanced stages of primary lymphedema were examined with magnetic resonance lymphangiography. A 18 mL of gadodiamide and 2 mL of mepivacainhydrochloride 1% were subdivided into 10 portions and injected intracutaneously into the dorsal aspect of both feet. For MRL, a 3D spoiled gradient-echo sequence (Volumetric Interpolated Breathold Examination, VIBE) was performed. RESULTS: The beaded appearance of lymphatic vessels extending from the injection site was detected in all 16 lower extremities (100%). In 10 lower extremities (63%), lymphatic vessels of the upper leg could be visualized. A contrast enhancement was observed in 10/16 inguinal lymph node groups (63%). In 12 lower extremities (75%) collateral vessels with dermal back-flow areas between lymphatic vessels were seen. CONCLUSION: Magnetic resonance lymphangiography is safe, technically feasible, and assists the clinician in the therapeutic planning of patients with clinically advanced stages of primary lymphedema by imaging the pathologically modified lymphatic vessels and accompanying complications non-invasively.

Magnetic resonance imaging of lymphatic vessels without image subtraction: a practicable imaging method for routine clinical practice?

OBJECTIVE: To assess the feasibility of a time-efficient, high-resolution magnetic resonance lymphangiography (HR MRL) protocol without image subtraction for the detection of lymphatic vessels in patients with primary and secondary lymphedema. METHODS: Three consecutive patients with lymphedema of the lower extremities (2 primary bilateral, 1 secondary unilateral) underwent HR MRL without image subtraction. An amount of 9 mL of gadodiamide and 1 mL of mepivacaine hydrochloride 1% were subdivided into 5 portions and injected intracutaneously into the dorsal aspect of each foot outside the scanner before image acquisition. Magnetic resonance imaging was performed with a 1.5-T system equipped with high-performance gradients. For HR MRL, a 3-dimensional, spoiled gradient-echo sequence (Volumetric Interpolated Breath-hold Examination) was used. The extent and distribution of the lymphedema was evaluated using a heavily T2-weighted, 3-dimensional turbo-spin echo sequence. RESULTS: The HR MRL bilaterally detected the inguinal lymph nodes and the lymphatic vessels in the lower and upper leg in the 2 patients with primary lymphedema. In the patient with left-sided secondary lymphedema, the inguinal lymph nodes and the lymphatic vessels in the lower and upper leg were depicted on the right side. The diameter of the displayed lymphatic vessels varied between 1 and 5 mm. Three-dimensional, maximum-intensity projection images of different angles of view provided detailed outlining of the lymphatic vessels and differentiation from veins, which showed a lower signal intensity. CONCLUSION: The HR MRL without image subtraction is safe, technically feasible, and has the potential to become a diagnostic imaging tool in daily clinical practice because of its time efficiency.

High-resolution MR lymphangiography in patients with primary and secondary lymphedema.

OBJECTIVE: The objective of our study was to evaluate the feasibility of high-resolution MR lymphangiography with intracutaneous injection of gadodiamide, a commercially available, nonionic, extracellular paramagnetic contrast agent, for the visualization of lymphatic vessels in patients with primary and secondary lymphedema. CONCLUSION: High-resolution MR lymphangiography is safe, is technically feasible, and has the potential to become a diagnostic imaging tool for patients with lymphedema.

Postoperative lymphoceles: detection with high-resolution MR lymphangiography.

Lymphoceles that do not resolve spontaneously or with treatment may be a major problem associated with a high degree of morbidity. Several imaging studies, including ultrasonography, computed tomography, magnetic resonance (MR) imaging, lymphography, lymphoscintigraphy, and intraoperative lymphatic mapping have been proposed to delineate lymphoceles before treatment. The present report describes the successful detection of three lymphoceles of the inguinal region with leaking lymphatic vessels by means of high-resolution MR lymphangiography.

Indirect magnetic resonance lymphangiography in patients with lymphedema preliminary results in humans.

PURPOSE: To assess the feasibility of indirect magnetic resonance (MR) lymphangiography with intracutaneous injection of gadodiamide, a commercially available, non-ionic, extracellular paramagnetic contrast agent for the detection of lymphatic vessels in patients with lymphedema. MATERIALS AND METHODS: In 2005, three patients with lymphedema of the lower extremities (1 primary, 2 secondary) were referred by the Foeldi Clinic for Lymphology for indirect magnetic resonance lymphangiography. 4.5 mL of gadodiamide and 0.5 mL of mepivacainhydrochloride 1% were injected intracutaneously into the dorsal aspect of each foot. MR imaging was performed with a 1.5-T system equipped with high-performance gradients. For indirect magnetic resonance lymphangiography, a 3D Fast Low Angle Shot (FLASH) sequence (TR/TE: 5.1/1.23; flip angle: 25; matrix: 448 x 448; bandwidth: 330 Hz/pixel; 6/8 rectangular field of view with a maximum dimension of 500 mm; slices: 88; voxel size: 2.0 mm x 1.0 mm x 1.0mm; acquisition time: 0 min 31 s) was used. RESULTS: Indirect magnetic resonance lymphangiography depicted lymphatic vessels of the lower and upper leg, and inguinal lymph nodes in all three patients. After 5 min of contrast material application, concomitant venous enhancement was detected. Collateral vessels with dermal back-flow were seen in two patients. A lymphocele in the inguinal region with the afferent lymphatic vessel was depicted in one patient. CONCLUSION: In the presented small study group, indirect magnetic resonance lymphangiography was technically feasible, and no complications were observed after intracutaneous injection of gadodiamide. Visualizing the lymphatic vessels and accompanying complications non-invasively and without the use of radiation, the presented method has the capability to become a routine diagnostic imaging tool in patients with primary and secondary lymphedema. The method is not able to characterize lymph node morphology, but could provide additional information about the lymphatic vessels when lymph nodes are examined, e.g. with super-paramagnetic iron oxide particles.