CLINICAL VIGNETTE - Lymphedema

UCLA Department of Medicine

Bruce Landres, M.D.

Introduction

Lymphedema represents the failure of the lymphatic system to adequately drain lymphatic fluid from the interstitial tissue. Although lymphedema can occur in any part of the body, the term is generally used to represent an accumulation of fluid and subsequent distortion of a limb. In the earlier medical literature, this generally referred to a congenital defect in the lymphatic system. In a more contemporary review, lymphedema is significantly more common as a consequence of surgery or radiation leading to the destruction of lymphatic channels. There is also a third cause: the parasitic infestation, filariasis. Since it is rarely seen in the U.S., this etiology will not be discussed. This case report presents a congenital albeit late onset (praecox) form of lymphedema.

Case Report

A 28-year-old male presented for the first time for follow-up after a bout of cellulitis of the right lower extremity. The patient had had an uneventful childhood and was well until the age of 17 years when he presented with cellulitis of the right calf. At that time there was no prior swelling of the limb and no apparent wound or site of entry for the infection. However, the severity and persistence of the infection prompted hospitalization and treatment with intravenous antibiotics. In the aftermath of that infection, the patient had chronic swelling of the affected limb and recurrent minor bouts of cellulitis in that leg. Because of this, he underwent a lymphangiogram in at age 20, which demonstrated right lower extremity soft tissue irregular swelling, with absent lymphatic contrast consistent with lymphedema. Over the subsequent eight years the patient had a total of four additional infections, requiring antibiotics but no further hospitalizations.

The patient's family history was unremarkable for similar disease.

The patient's physical examination was unremarkable, except for a brawny pitting edema, judged to be 2-3/4+ in severity involving the right lower extremity from the knee down, with hyperpigmentation and a right mid-calf diameter of 30 cm compared to left mid-calf diameter of 26 cm. There was no inguinal or other adenopathy.

A lymphoscintigraphic study of the right lower extremities showed a reduced pattern of flow consistent with obstructive changes in that leg. Reduced numbers of nodes and nodal uptake was felt to represent congenital absence of lymphatic tissue.

Discussion

The causes of lymphedema, and the subsequent development of a swollen limb, are commonly classified as either congenital absence of lymphatics, hypo-or hyperplasia of lymphatics, or obstruction/destruc-tion of lymphatics. The incidence of congenital lymphedema in the population younger than 20 years of age is 1.15 per 100,000 with female predominance in 87% of the cases.1 In contrast the overall incidence of secondary lymphedema in the general population is reported to be more than four hundred times more common than congenital cases, and is seen in 5 persons per 1,000. Lymphedema has been reported to occur in 2%-60% of breast cancer patients in long-term follow-up. Lymphedema reportedly occurs in as high as 56% of patients following groin or pelvic surgery depending upon the treatment used.2,3

Congenital absence of lymphatics, or Milroy's Disease, leads to the onset of progressive swelling of a limb at birth with a familial occurrences of the condition, but no other anomalies. The etiology has been traced to the long arm of chromosome 5q. Interestingly the gene for vascular endothelial growth factor has been mapped to this same region of chromosome 5q, and there are data to suggest that a missense mutation in this gene may also be linked to lymphedema.4

Another type of primary lymphedema is lymphedema praecox or Meige's lymphedema. Generally this occurs prior to the age of 35 years most commonly at or around the time of puberty.5 This is reported to account for 94% of primary lymphedema.6 Some forms of this lymphedema are associated with a linkage to chromosome 16q.4

A third form of primary lymphedema, tarda, occurs after age 35 and represents approximately one in sixteen cases of primary lymphedema.

Surgeries for cancer of the breast, prostate, bladder, uterus or skin can remove or disrupt lymphatics through lymph node dissection, and represent a much more common cause of lymphedema. Radiation therapy causes fibrosis of involved areas, compromising normal lymphatic drainage and collateral pathways. Additionally, radiation to nodes can compromise an individual's later response to infection. Tumor growth, either primary or metastatic, can serve as a physical obstruction to lymph drainage causing secondary edema.

Also, infection, such as lymphangitis or cellulitis increases local blood flow and capillary permeability, thereby increasing the fluid load in a compromised lymphatic system. This leads to fibrosis, increasing inability of the lymphatic vessels to drain the limb and more edema.5 This process creates a protein rich environment in the affected edematous limb which promotes infection and worsening of the edema.

Notwithstanding the varieties of lymphedema, the consequences can be profound. The progression of the edematous limb to disfigurement can have severe psychological impact on the patient. There can also be an associated numbness and tingling, discomfort and even pain. The patient may have a sensation of tightness of the skin and heaviness of the limb. Loss of mobility of the limb, hyperkeratinosis, compromised wound healing, and recurrent skin infection are also possible.5

Rockson reports an incidence of acute cellulitis in 6% of patients followed over a 42-month period.6 In these cases the most common organism is non-group A beta-hemolytic streptococci. Beta-lactam agents, in particular penicillin G, have been the mainstay of treatment in these cases. However, this treatment is largely empirically based due to a lack of controlled trials.7

The diagnosis of lymphedema is made clinically and confirmed radiographically. Lymphedema should be considered in newborns and young adults with an unexplained edematous limb, the presentation of a brawny edema, or recurrent cellulitis in a chronically edematous limb. It may be necessary to use venous doppler studies and venography in the clinical setting to rule out venous obstructive disease as the cause of edema. Myxedema with pretibial edema can also be ruled out by a simple blood test.

The diagnosis of lymphedema is easily confirmed using isotopic lymphography studies, such as lymphoscintigraphy or lymphangioscintigraphy which have supplanted oil contrast lymphography and are considered to be the gold standard.6 These studies provide superior imaging of the lymphatics, as well as reduce the risk of anaphylactic reaction which can be seen when contrast dyes are used.

Magnetic resonance imaging and computerized tomography may also help by demonstrating the absence of edema within the muscular compartment and the honeycomb distribution of edema within the epifascial plane, along with thickening of the skin.6 There is also an anatomic delineation of lymphatic and nodal architecture.

When there is a question of malignancy, lymph node biopsy is a consideration. However, this may exacerbate a lymphedematous state by further compromising lymphatic drainage. In such a presentation, fine needle aspiration of a suspicious lymph node may provide a reasonable alternative.8

Once the diagnosis has been established, there are a variety of approaches to the treatment of lymphedema which have been shown to be effective. Generally, however, the purpose of therapy is palliation, not cure.
Bernas described the need for a combination of physical therapies involving skin care, exercises, multi-layered bandage wrapping and manual lymphedema treatment, with the later addition of compression by elastic stockings.8 He stressed that manual lymphedema treatment is directed towards massage of areas proximal to the lymphedematous area, and then directing the treatment more distally. Exercises have been shown to reduce the volume of a limb swollen with lymphedema.

Other potential therapies include intermittent pneumatic compression after manual lymphedema treatment, using a sequential pump and tight fitting elastic stockings, elevation of the affected limb which seems to be effective in the early stages of the disease, and the aggressive use of antibiotics both prophylactically and to treat infections. Diuretics are felt to be useful in the short-term, but long-term administration is felt to be of marginal value and even deleterious.5,8

Several therapeutic modes are felt to be either experimental or of questionable value. Undirected deep massage may actually be harmful to the remaining lymphatics if done too forcibly. The application of heat to the affected limb in addition to compression is felt to be experimental but possibly helpful. The medication class, benzopyrones (coumarin) are thought to activate extra-lymphatic absorption of tissue proteins and stimulate the remaining lymphatic collectors but the medications effects have yet to be proven. Local injection of hyaluronidase to help loosen the extra-cellular matrix is of doubtful value.8

It is important to note that no special diet is helpful for lymphedema. However, obesity has long been reported to be both a precipitant and an exacerbating agent for lymphedema, so weight reduction to ideal body weight is a mainstay of treatment.4,6

It is important to remember that lymphedema is a lifelong disease with potential disfiguring consequences. Psychosocial support and quality of life assessment should be an integral part of any treatment program.5,8

The use of surgery for correction appears to be controversial. The simplest operation is the debulking of the excess skin and lymphedematous tissue to improve both the disfigurement and weight of the limb. However, this may interfere with later CPT. Microsurgery techniques hold promise but require an experienced surgeon. Also lymph-venous and lymph nodal venous shunt show promise especially when done early and prior to irreversible fibrosclerosis.8

Campisi argued that microsurgical creation of lymphatic venous anastomoses is more effective than CPT.9 In 665 cases, 87% noted subjective improvement, and 83% showed a 67% reduction in volume with observable results after the first day of surgery. 85% of the patients were able to discontinue more conservative methods of treatment (e.g. CPT). There was also an 87% reduction in the incidence of cellulitis following surgery over an average follow up of seven years. Lymphoscintigraphy visualized flow through the lymphatic venous grafts even 15 years after the operation. However, Campisi did not discuss any complications noted from the surgery. He also did not mention the fact that his conclusions were based on outcomes of surgeries performed by surgeons with extensive experience in this type of surgery. Additionally, he did not report the basis for selection for surgery and whether his numbers represented all patients or just a small subset of individuals with lymphedema.9

In fact Araujo reported that only 30% of individuals with lymphedema may be suitable for lymphatic venous anastomoses and only half of these operations are successful at 5 years.10 Hafez reported that surgery is indicated in only 10% of patients with primary or secondary lymphedema. A large variation exists in the efficacy of surgery to ameliorate lymphedema. The success rate ranged from 30%-74% with a failure rate as high as 25%.2

Conclusion

Although primary lymphedema is uncommon, secondary lymphedema has become more prevalent as we become more effective in treating various cancers. Studies have shown that physicians seldom discuss the potential risk of lymphedema with patients prior to a surgical procedure. In one study, seven of ten physicians did not feel adequate to provide treatment for lymphedema.3 Since lymphedema is a condition with significant psychological and physical morbidity, physicians should be aware of it as a potential unfortunate consequence of surgical and radiation therapies and move aggressively to minimize its consequences to the patient. Medical management of this condition seems to be the treatment of choice with a smaller subset of individuals benefiting from surgical intervention.

REFERENCES

Harel L, Amir J, Nussinovitch M, Straussberg R, Varsano I. Lymphedema praecox seen as isolated unilateral arm involvement: case report and review of the literature. J Pediatr. 1997 Mar;130(3):492-494.
Hafez HM, Wolfe JH. Lymphedema. Ann Vasc Surg. 1996 Jan;10(1):88-95.
Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer. 2001 Sep 15;92(6):1368-1377.
Brice G. The genetics of primary lymphoedema. British Lymphology Society Annual Conference Proceedings 2000. Accessed 9/1/2002. Kelly D. A Primer on Lymphedema. 2002. Pearson Education; New Jersey. p. 165.
Rockson SG. Lymphedema. Am J Med. 2001 Mar;110(4):288-295.
Woo PC, Lum PN, Wong SS, Cheng VC, Yuen KY. Cellulitis complicating lymphoedema. Eur J Clin Microbiol Infect Dis. 2000 Apr;19(4):294-297.
Bernas MJ, Witte CL, Witte MH. The diagnosis and treatment of peripheral lymphedema: draft revision of the 1995 Consensus Document of the International Society of Lymphology Executive Committee for discussion at the September 3-7, 2001, XVIII International Congress of Lymphology in Genoa, Italy. Lymphology. 2001 Jun;34(2):84-91.
Campisi C, Boccardo F. Lymphedema and microsurgery. Microsurgery. 2002;22(2):74-80.
Araujo JA, Curbelo JG, Mayol AL, Pascal GG, Vignale RA, Fleurquin F. Effective management of marked lymphedema of the leg. Int J Dermatol. 1997 May;36(5):389-392.

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