Pathology of lymphedema

Diagnosis of chronic progressive lymphoedema (CPL) in draught horses, including the Belgian Draught Horse, is mainly based on clinical evaluation of typical lower limb lesions. A deficient perilymphatic elastic support, caused by a pathological elastin degradation in skin and subcutis, has been suggested as a contributing factor for CPL. Elastin degradation products induce the generation of anti-elastin Ab (AEAb), detectable in horse serum by ELISA. For a clinically healthy group of draught horses, a significantly lower average AEAb-level than 3 clinically affected groups (mild, moderate and severe symptoms) was demonstrated previously. To improve CPL-diagnosis, we evaluated the AEAb-ELISA as an in vitro diagnostic aid in individual horses. Test reproducibility was assessed, performing assays independently in 2 laboratories on a total of 345 horses. Possible factors associated with AEAb-levels (age, gender, pregnancy, test lab and date of blood collection) were analyzed using a mixed statistical model. Results were reproducible in both laboratories. AEAb-levels in moderately and severely affected horses were significantly higher than in healthy horses. Nevertheless, this was only demonstrated in barren mares, and, there was a very large overlap between the clinical groups. Consequently, even when a high AEAb cut-off was handled to obtain a reasonable specificity of 90%, a very low sensitivity (21%) of AEAb for CPL-diagnosis was obtained. Results on the present sample demonstrate that the described ELISA procedure is of no use as a diagnostic test for CPL in individual horses.

Lymphedema is a manifestation of lymphatic system insufficiency. It arises from primary lymphatic dysplasia or secondary obliteration after lymph node dissection or irradiation. Although improvement of swelling can be achieved by comprehensive non-operative therapy, treatment of this condition requires lifelong care and good compliance. Recently molecular-based treatments using VEGF-C have been investigated by several researchers. We designed the present study to determine whether the therapeutic efficacy of implanted human adipose-derived stem cells (hADSCs) could be improved by applying a gelatin hydrogel containing VEGF-C (VEGF-C hydrogel) to the site of tissue injury in a lymphedema mouse model. Four weeks after the operation, we evaluated edema and determined lymphatic vessel density at various post-operative time points. Mice treated with hADSCs and VEGF-C hydrogel showed a significantly decreased dermal edema depth compared to the groups of mice that received hADSCs only or VEGF-C hydrogel only. Immunohistochemical analysis also revealed that the hADSC/VEGF-C hydrogel group showed significantly greater lymphatic vessel regeneration than all the other groups. hADSCs were detected in the implantation sites of all mice in the hADSC/VEGF-C group, and exhibited a lymphatic endothelial differentiation phenotype as determined by co-staining PKH-labeled hADSCs for the lymphatic marker LYVE-1. Our results suggest that co-administration of hADSCs and VEGF-C hydrogel has a substantial positive effect on lymphangiogenesis.

To determine the presence, degree, and extent of lymphatic, elastic, and collagen fiber alterations in dermatochalasis (DC) specimens.

Case control study of patients with DC compared with age-, gender-, and site-matched controls.

A total of 25 eyelid specimens were studied; 15 of these were blepharoplasty specimens (experimental) and 10 were entropion/ectropion specimens of patients without DC (controls).

The number and maximal dilation of lymphangiectasia was measured by light microscopy, immunohistochemistry with lymphatic marker D2-40, and elastic tissue content by Verhoeff–van Gieson histochemistry. The number of macrophages was compared between patients with DC and controls in CD68 immunostained specimens.

Lymphatic density, edema, and inflammation.

Dermatochalasis eyelid specimens showed increased lymphangiectasia density (5.6 vs. 2.4 lymphatics/high power field; P<0.05), maximal lymphatic dilation (127 vs. 51.5 μm; P<0.05), loss of elastic fibers (2.2 vs. 8.9 fibers/high power field; P<0.05), and greater disruption of collagen networks and edema compared with controls (increased stromal collagen bed of 752 vs. 269 μm; P<0.05; increased intercollagen space of 32.5 vs. 11.8 μm; P<0.05). Macrophages were present in greater quantities in DC specimens (28.6 vs. 11.9 macrophages/high power field; P<0.05).

Patients with DC show an increase in number and maximal dilation of lymphatic vessels in conjunction with widely spaced collagen bundles. This finding coexists with loss of elastic fibers, components known to be essential to the structure and function of the lymphatic system. Governed by macrophages, the pathogenesis of DC may begin with subclinical inflammation leading to elastolysis and secondary lymphostasis.

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Katz E, Dugan NL, Cohn JC, Chu C, Smith RG, Schmitz KH. Weight lifting in patients with lower-extremity lymphedema secondary to cancer: a pilot and feasibility study.

To assess the feasibility of recruiting and retaining cancer survivors with lower-limb lymphedema into an exercise intervention study. To develop preliminary estimates regarding the safety and efficacy of this intervention. We hypothesized that progressive weight training would not exacerbate leg swelling and that the intervention would improve functional mobility and quality of life.

Before-after pilot study with a duration of 5 months.

University of Pennsylvania.

Cancer survivors with a known diagnosis of lower-limb lymphedema (N=10) were directly referred by University of Pennsylvania clinicians. All 10 participants completed the study.

Twice weekly slowly progressive weight lifting, supervised for 2 months, unsupervised for 3 months.

The primary outcome was interlimb volume differences as measured by optoelectronic perometry. Additional outcome measures included safety (adverse events), muscle strength, objective physical function, and quality of life.

Interlimb volume differences were 44.4% and 45.3% at baseline and 5 months, respectively (pre-post comparison, P=.70). There were 2 unexpected incident cases of cellulitis within the first 2 months. Both resolved with oral antibiotics and complete decongestive therapy by 5 months. Bench and leg press strength increased by 47% and 27% over 5 months (P=.001 and P=.07, respectively). Distance walked in 6 minutes increased by 7% in 5 months (P=.01). No improvement was noted in self-reported quality of life.

Recruitment of patients with lower-limb-lymphedema into an exercise program is feasible. Despite some indications that the intervention may be safe (eg, a lack of clinically significant interlimb volume increases over 5mo), the unexpected finding of 2 cellulitic infections among the 10 participants suggests additional study is required before concluding that patients with lower-extremity lymphedema can safely perform weight lifting.