Guidelines for the Diagnosis and Treatment of Lymphatic Disorders
PART III
General considerations
Lymphedema is a chronic disease, frustrating both for the patient and the doctor. It is caused by a defect in the lymphatic system leading to a build-up of lymph in the interstitial space, mainly at a suprafascial level in the first instance but then throughout the subcutaneous tissues. The lymphatic system s prime function is to remove large molecules and water from the interstitial space and to allow a turnover of the cells of the system.1
From a physio-pathological point of view lymphatic insufficiency can be classified as dynamic or mechanical. Dynamic (or high- capacity) insufficiency occurs in an intact lymphatic system which must deal with a protein load higher than its capacity. Mechanical (or low-capacity) insufficiency is caused by either primary or secondary damage to the lymphatic system, which subsequently cannot deal with a normal protein load.2 The proteins stimulate the influx of mast cells and neutrophils, triggering a process of non-specific granulation, which in time leads to interstitial fibrosis with irreversible structural damage.3
Epidemiology
It is difficult to obtain a clear idea of the prevalence of lymphedema worldwide, partly because it is always hard to make an immediate and specific diagnosis. Epidemiological data however shows that this is a widespread complaint throughout the world, with no major differences in its clinical manifestations. A third of the worlds population has some sort of edema, the most serious being lymphedema – there are 150 million recorded cases. The majority of these cases (45 m) are due to parasites; postoperative lymphedema or trauma is responsible for another 25 m, and between 5 and 20 m are primary lymphedema.4,5 The risk of filaria infection and its consequences probably involves 2 million people throughout the world.5
In Europe, Spain has a high incidence of lymphedema in women (84%) between the ages of 45 and 59.
Primary lymphedema makes up 79% of cases, secondary lymphedema 21%; 76.5% of primary lymphedema is in patients under the age of 45, and 80% of secondary lymphedema cases are over the age of 45. The incidence of secondary lymphedema is highest in orthopedics (33%), followed by trauma (25.5%) and malignant tumors (18.9%) with 90% of these post-mastectomy, which accounts for 6-30% of lymphedema.6 The upper limbs are affected in 21.7% and the legs in 79%.7
In Italy, there is little data on primary lymphedema, which probably accounts for 30-40% of the total. Forty percent of secondary lymphedema is post-mastectomy.8-10 Reliable epidemiological figures on lymphedema are still scant, both in Italy and elsewhere.
Prevention
Primary lymphedema is a clinical condition that occurs suddenly and cannot, therefore, be predicted. However, secondary lymphedema can be clinically predicted, although not when it is likely to occur.
Authoritative proposals on the prevention of lymphedema only concern secondary lymphedema and are mainly aimed at surgeons (for example, type of incision and surgical technique, preserving the lymphatic drainage areas of most use to the limb), or oncologists (moderately aggressive radiotherapy, if possible).
The proposals involve analysing the lymphatic system before postoperative lymphedema arises, by isotopic lymphangiography within 2-3 months of the operation to study the anatomy and the residual function of the limb at risk,11 and the prevention of infection (dermato-lymphangio-adenitis) by administering lifelong benzatin- penicillin.12
In most cases current strategies aim at preventing the complications of lymphedema, infections in particular. However, we believe it should be aimed primarily at preventing gross progression, that is, the increase in size of the affected limb. This is only possible if, as the ISL Consensus Document officially recognised in 1995,13 a complete long-term physical treatment protocol is promptly devised and administered, modifying it to suit the individual clinical picture. It should include all the advice the patient needs (such as lifestyle advice, exercise at home, psychotherapy, self-help). This applies to any type of lymphedema but is particularly fruitful early in the clinical course when the edema is soft and either intermittent or remitting. It is abundantly clear that prevention of lymphedema means stopping it happening, if possible, or at least preventing progression. Where complications have not yet set in, these aims can be achieved if the patient undergoes early treatment, which includes kinesitherapy, meaning lymph drainage, and pressure therapy, and compression (with multiple bandages, elastic bandages or stockings), as well as “lymphotropic” drugs. The prevention of secondary lymphedema also depends on the availability of skilled kinesitherapists, on the patient’s expectations and ability to cooperate, and on cost.14-17
Recommendations
Give patients information about their disease and on the probability of lymphedema, so they are ready to deal with the problem. Early diagnosis and physiotherapy are basic steps in the treatment of lymphedema. In oncological surgery and radiotherapy the possibility of secondary lymphedema must be borne in mind. Grade C
Clinical and instrumental diagnosis
Clinical diagnosis
Often, a detailed clinical history and objective examination can reveal the cause of edema and suggest the diagnosis of lymphedema. Further thorough instrumental examinations should then be scheduled. Although the etiology of primary and secondary lymphedema differs, the clinical picture and the objective signs of the disease are often similar.13,18 A clinical history can exclude the existence of underlying pathologies – cardiac, renal, and so on – and establish the date of onset, how it appeared and its course up to the present time.
The patient with lymphedema must be examined in the standing and lying positions. The examination should assess the condition of the skin, the distribution of the edema, the existence of spontaneous or evoked pain, the depth of skin folds, any lymphatic exudation, whether there is a network of varicose veins or lymphatic varices, lymphadenopathy, signs of lymphangitis or other skin lesions, past or present. Palpation helps to assess spontaneous or evoked pain and the consistency of the edema – the examining doctor might look for pitting, and the Stemmer sign, and measure the limb.19 It is also important to examine all lymph nodes that can be reached, and note the patient’s weight and height.
Certain “key points” are often employed in the clinical classification of lymphedema of the limbs. These are: the temporo- spatial distribution and severity of the edema, the condition of the skin and adnexa, limb function, present and past lymphangitis and lymphatic exudate.18 The following classifications have been proposed: etiopathogenic, anatomical, functional and clinical.
Lymphedema is normally divided into 2 broad groups:
– primary, due to dilatation, stenosis or aplasia of the lymphatic collector vessels;
– secondary, caused by extrinsic lesions arising from surgical removal of the lymph nodes or damage to lymphatic vessels.
Both primary and secondary lymphedema may become malignant.
A few examples are given here of the different classifications used today: criteria committee of the N.Y. Heart Association (1964), Zierman (1996), Battezzati-Donini (1967), Howard (1968), Foldi (1971,1982), Cordeiro (1983), Martorell (1972), Hunt (1972), Kinmonth (1982), Pietravallo (1988), operative classification (Donini 1992, modified in 1998), Campisi (1997).
In these guidelines we have mainly used the Donini clinical, anatomical and functional operative classification (1992, modified in 1998) which organises lymphedema into 5 clinical stages. This classification is the result of a critical analysis of the various existing classifications of lymphedema of the upper limb and relating the clinical and hlstopathological pictures.
Alongside this classification is the modified Battezzati-Donini etiopathogenic classification (Tosatti 1967) which classifies lymphedema on the basis of the anatomical or functional damage to the lymphatic system as diseases involving the collecting system, diseases due to altered lymphogenesis and absorption, and diseases of mixed etiopathogenesis.
Instrumental methods
Currently, lymphoscintigraphy and echography are the techniques most used in the diagnosis of lymphedema in the lower limbs. Other methods include venous echo Doppler, microlymphangiography, CT and MRI scans, venography, lymph node biopsy and lymphography (in selected cases and in specialized centers).13 The diagnosis of lymphedema was enormously facilitated by the introduction of Kinmonth’s technique for direct incannulation of lymphatic vessels, and the development of lymphoscintigraphic radiodiagnosis.20,21
Lymphoscintigraphy with 99mtechnetium in the form of radiolabeled colloid is used for morphological and functional examination of the lymphatic system of the lower limbs.22 Ultrasound examination (echography) of soft tissues shows up free lymph in the suprafascial and interstitial areas.13,20,23-27
Other examinations serve to complete the diagnosis when further investigations are made in specialized centers. CT scan with contrast medium, venography, lymphography and lymph node biopsy help exclude complex congenital malformations or neoplastic diseases.28 Fluorescent microlymphangiography is a non-invasive metho\d for assessing the spontaneous lymphatic drainage of specific substances injected intradermally.25
Recommendations
First level diagnostic examinations: US of the soft tissues and echoDoppler
Second level examinations: radioisotopic lymphoscintigraphy
Third level examinations: fluorescent microlymphangiography, venography CT, MRI scans and other instrumental examinations. Grade A
Treatment
Lymphedema of the limbs is mainly conservative, surgery being reserved for selected cases of advanced disease.
Conservative treatment
This heading comprises pharmacological measures and physical compression. Compression includes various procedures, such as manual lymphatic drainage (MLD), compression, and pressure therapy (PT), elevation and heat treatment.29 Drugs include the benzopyrones such as coumarin which has a direct effect on inflammation, and especially on the macrophages;if used on a continuing basis, it accelerates protein degradation thus activating extra-lymphatic absorption.30 Benzopyrones are used at every stage of lymphedema, whether primary or secondary. There are reports of severe hepatotoxicity of high-dose synthetic coumarin given to treat secondary lymphedema.31 Antibiotics and antimycotics are used if infective complications arise (lymphangitis);the use of diuretics is not recommended as they eliminate more water than proteins.32
Physical treatment should not be limited to one type, but should involve a combination of different treatments, selected depending on the stage of the lymphedema and the strategy applicable at the time.33,34 Combined physical therapy is divided into 2 stages. The first is aimed at reducing the interstitial lymphatic load and, consequently, reducing the size of the limb; while the second stabilises and if possible improves on the results.35
The first stage combines lymphatic drainage, pressure bandages, physical exercise and meticulous skin care. In the second stage patients are required to wear elastic stockings on a daily basis, to do specific exercises and to ensure meticulous skin care. Pressure therapy is sometimes recommended in this second stage.35-38 Elevation is certainly effective in reducing edema.39 Heat treatment is widely used, but its effectiveness is still under study.40
Recommendations
It is important to use more than one type of physical treatment, and to combine the different methods strategically, depending on the stage of the lymphedema. Grade B
Surgery
Many techniques are currently used in the surgical treatment of lymphedema of the limbs. The physiological approach aims to restore the normal lymphatic flow by creating venous-lymphatic and lymphatic- venous-lymphatic anastomoses, and uses autologous lymphatic tissue transplants with lyrnpho-lymphatic anastomosis.41
The radical approach does not follow a strict physiopathological principle, but involves destroying large areas of skin, subcutaneous and fascial tissue. Combinations of these two approaches use both concepts. Thompson’s operation is the precursor of these methods.
Among the excision types of operation, the Charles operation has proved effective in some patients whose extensive edema did not respond to conservative treatment and who had severe trophic skin alterations.42,43 The Thompson operation has been tested clinically on a wider scale, with encouraging long-term results, though lymphangiography did not document the presence of new anastomoses between the superficial and deep systems. In selected cases, it may be effective in reducing late edema, thought serious postoperative infective complications are a risk.4445
The Homans operation has given better results in serious cases, with functional recovery of the limb in primary lymphedemajin secondary forms the results tend to differ depending on the various case series.46,47
Lymph liposuction removes the layers of fluid, and can halve the edema within a year. It is much less invasive than other methods.48
The principal of all the strategies derived from these main techniques is the creation of lymphatic-venous anastomoses. This approach was initially very successful in lymphology but there are doubts about the long-term effectiveness, because it is not easy to prove long-term patency. However, in some series 74% of patients still enjoyed an improvement one year after treatment.49,50 Other related methods have been largely abandoned because of the poor one- year results and the attendant complications. These include lymphatic graft;51 the Kinmorith technique or mesenteric bridge;23 and the Goldsmith omental transposition method.52,53
Recommendations
The best indication for surgical excision is the loss of limb function due to excessive lymphedema resistant to conservative treatment. A combination of lymph liposuction and a modified Hornans operation gives best results, though international studies limited. No multicenter studies have been done to document the real effectiveness of the “derivative” methods.
Surgery should in any event be carried out in highly specialised hospitals by surgeons with specific experience. Grade C
Quality of life
In Italy, most lymphedema is managed by specialists such as angiologists, cosmetic and plastic surgeons, physiatrists, general and vascular surgeons, arid microsurgeons, who each tend to view the problem from their own point of view. This leads to a confused approach to treatment and, therefore, a poor quality of life for the patient.
Primary lymphedema and secondary forms consequent to cancer surgeiy – especially breast cancer – are reference conditions for illustrating the repercussions on the patient’s quality of life.54 Recent surveys agree that the patient tends to worry more about the difference in size of the 2 limbs than the actual symptoms of the edematous limb.55 Edema of the hand causes greater mental distress than edema of the whole arm because that can be “hidden”.
In the case of post-mastectomy lymphedema, the swollen limb can be a real handicap, especially if the main side is affected. It affects gross movements such as washing, doing one’s hair, putting on a blouse, washing up;it also impedes finer movements such as fastening a necklace or writing, and chores or hobbies, such as ironing, carrying heavy objects, gardening, and so on.
The quality of life of a patient suffering from lymphedema depends on early diagnosis, ample information and treatment that best meets the patient’s needs. Good results are hard to achieve because of the lack of centers specialised in treating lymphedema, the lack of schools or courses for specialist training in lymphatic diseases, the high cost of treatment and its lifelong duration. Other specific constraints, mainly compliance, further reduce the chances of success.
Patients’ approval and understanding of the treatment strategy makes for 40% of its success. Esthetic considerations (asymmetry of the limbs), functional damage (inadequacy or loss of some functions) and relational problems (embarrassment with the partner or at work) are at the heart of the emotional reactions to the disease.
The patient’s acceptance of the various treatment options can at times be an obstacle for the lymph specialist. MLD and PT are the preferred methods even though they must be repeated regularly. In contrast, patients find it harder to tolerate wearing bandages or support hose. Although there is no substitute for them, provided they are appropriately prescribed and worn properly, patients dislike their appearance, and consider them a sign of the disease;also, they must be worn every day, at rest and while doing exercises, such as decongestant movements.
The patients own social and family environment plays an important role in compliance. The psychological support and encouragement to self-help which a patient may receive in the family must be followed up by the family’s active participation in caring for the affected limb (MLD, bandages, helping with decongestant exercises), under the guidance and instructions of the lymph specialist.34,54-57
Recommendations
Early diagnosis, taking into account the pathogenic factors
Check whether adequate treatment had been attempted before this diagnosis
An individual treatment strategy should be proposed taking account of the clinical stage and the patient’s requirements. Grade B
TABLE XVII. -Anatomical-clinical classification of lymphatic malformations.
Lymphatic malformations
Although congenital malformations of the lymphatic system are rare, they are highly disabling as they can cause severe functional and esthetic disorders. Congenital malformations of the lymphatic system arise from anomalies of the embryonic lymphatic capillaries or of the main lymphatic vessels of the limbs, head and chest.58 They occur mainly in peripheral areas, especially the legs, but forms involving the neck and face, chest and pelvis are also reported.59,60
A useful anatomo-pathological classification distinguishes capillary types from trunk types according to which part of the lymphatic tree is mainly affected (Table XVII).
Lymphatic capillary malformations are commonly known as lymphangioma. There is usually a dense network of microscopic lymphatic vessels in the skin, mucous membranes or soft tissues. They vary widely in size, from a small nodule to a large tumor-like mass. They are most frequent on the skull and face, especially on or around the tongue and eyebrows, in the axillary cavity and groin.58 Some have a diffuse, infiltrating appearance (diffuse tissue lymphangioma) whereas others present a microcystic structure with typical lymphatic vesicles (microcystic lymphangioma).
Lymphatic vessel malformations are caused by congenital abnormalities in the medium and large lymphatic trunks. Cystic hygromas are abnormal dilatations with sac-like ectasia of large collecting vessels at the main drainage points of the lymphatic system. They usually occur in the masseter, submandibular, lateral- cervical, axillary and inguinalregions.61 Mediastinal cystic hygromas are rare but can cause complications by compressing vital structures such as the trachea and central veins.
Congenital lymphedema involves massive, progressive edema in a limb, caused by hypoplasia or agenesia of the main peripheral lymphatic trunks, leading to blockage of lymphatic outflow and interstitial stasis.
TABLE XVIII. – Complications of lymphatic malformations.
TABLE XIX. – Diagnostic approaches to the patient with lymphatic malformations.
Schematically, it is also useful to distinguish pure lymphatic malformations, involving isolated alterations in the lymphatic vessels, and mixed lymphatic-venous forms in which there are congenital abnormalities of both the lymphatic circulation and the superficial and/or deep venous system.
The natural history of lymphatic malformations may vary widely. Lymphangiomas and cystic hygromas are usually present at birth and may grow gradually over the years, especially in concomitance with various factors and events, which may be hormonal, traumatic or infective. In some cases, there is a gradual involution of the lymphatic mass or sac after puberty.
Congenital lymphedema tends to manifest itself at birth, during childhood or adolescence, but sometimes becomes obvious only in adulthood. It progresses slowly. The most frequent complications are generally local (Table XVIII).
Clinical picture
The clinical picture of lymphatic malformations depends on the type and severity of the anatomical abnormalities, and the part of the body affected. Surface lymphangiomas appear as subcutaneous swelling or raised whitish skin patches with an irregular, warty surface. In their microcystic form, there are frequently translucent microvesicles containing serous fluid. They are often accompanied by dystrophic skin lesions.
Cystic hygromas appear as large subcutaneous swellings which tend to be soft and spongy. They float, and are fairly responsive to antigravity manipulations;they do not pulsate. If a complication such as intracystic hemorrhage sets in, they may become hard and bluish, creating problems of differential diagnosis
The first symptom of congenital lymphedema is a gradual increase in the size of a limb. There are sporadic and familial forms. They usually involve the lower limbs but, less frequently, the arms too. They may be unilateral or bilateral. Lymphatic edema is usually doughy in its initial stages, becoming progressively harder and fibrous. There is massive enlargement of the limb, especially in the acral regions, with little improvement when the limb is raised. In the advanced stages, complications may set in, such as hypertrophic skin lesions with verrucosis and pachyderma, eczema and exudative lymphangitis.
Diagnosis
The diagnostic tools for lymphatic malformations include ECD, MRI, lymphography and lymphoscintigraphy.62 The indications and the relative strengths of these tools for diagnosing lymphatic malformations are summarized in Table XIX.
The ECD examination is used first to exclude any alterations of the arterial and venous circulation, in order to confirm the clinical suspicion of lymphatic vessel malformation. Usually, lymphangiomas cause significant thickening of the skin, in which small cavities can be observed, giving a signal typical of fluid;these can be only slightly compressed with the probe, and the Doppler examination shows no flow. Ultrasonographic scan shows cystic hygromas as large expansive formations containing fluid;they vary in size, and sometimes have only one chamber, but are more often multilobulate, with thick, hyperechogenic walls. Color Doppler examination shows no arterial or venous blood flow.
In lymphedema, echocolor Doppler examination does not provide significant direct information on changes in the lymphatic system but gives a good picture of the superficial and deep venous circulation, showing up any association with congenital or secondary venous insufficiency.
MRI serves to assess the extent, the size and the anatomical relations of localised lymphatic malformations.63
Direct injection lymphography of the lymphatic cistern is essential in the case of cystic hygromas for a morphological study of the sac and especially for percutaneous scleroembolisation.
Ascending lymphangiography, carried out by cannulating a lymphatic vessel in the foot, is useful for investigating the anatomy of the lymphatic circulation in congenital lymphedema, only in patients with suspected lymphangiectesia. Some caution must be exercised because of progression of lymphedema noted after contrast lymphangiography.
Lymphoscintigraphy involves injecting radiolabeled albumin subcutaneously in the foot. It is used widely to study lymphatic drainage in peripheral lymphedema as it shows up obstructions, hypoplasia, and atresias in lymphatic vessels in a minimally invasive manner.
Treatment
Treatment strategy is based on a thorough preoperative diagnostic assessment and mainly depends on the type of lymphatic malformation, its extent and site.64
Treatment should be as conservative as possible, as the surgical removal of lymphatic malformations is accompanied by a high incidence of recurrences and often unacceptable esthetic effects. Table XX summarizes the treatment options for the various lymphatic malformations and indicates the strength of the recommendations.
Percutaneous sclerotherapy is the first-choice treatment for microcystic tissue lymphangioma, and especially for cystic hygromas, because it is non-invasive, and gives excellent clinical results, with complete regression of lymphatic vesicles and cisterns. The size of the lesion dictates the choice of the sclerosing medium;for small lymphangiomas and cystic hygromas polydocanol is preferred, whereas large lymph sacs need ethanol, ethibloc or picibanyl.65-67 A sclerosing injection must always be followed by selective locoregional compression, especially in the case of large lacunae.
TABLE XX. – Treatment of lymphatic malformations.
Surgery is recommended in diffuse tissue forms with a tendency to progress, and in localised peripheral forms, where radical surgical removal can be carried out without causing disfigurement or functional disability. In advanced lymphedema with a hugely swollen limb, cuto-lipo-fascectomy may be necessary to enable the patient to regain motor function of the limb.
The results with various operations to reconstruct the lymphatic system proposed in recent years, such as lymphatic-venous anastomosis, are not yet good enough to allow their routine use. In selected cases, even with lymphatic malformations, it may be useful to combine surgery and sclerotherapy to achieve the best functional and esthetic results.
References
1. Bergan JJ. Lymphedema: introduction and clinical evaluation. In: Handbook of Venous Disorders, Guidelines of American Venous Forum. North Way: Chapman-Hall Medical. 1996;33.p.569-79.
2. Foldi M,Casley-Smith JR. Lymphangiology. StuttgartNewYork: Schattauer Verlag;1983.
3. Rutili G, Arfors KE. Protein concentration in interstitia and lymphatic fluids from the subcutaneous tissue. Acta Physiol Scand 1989;99:1-8.
4. World Health Organization. Lymphatic filariasis Fact Sheet N 102 Rev September 2000.
5. Piller NB. The prevalence of leg, arm and facial swelling in a western population. Eur J Lymph 1997-1998;6:23.
6. Patrek JA, Meelan MC. Incidence of breast carcinomarelated lymphedema. Cancer Suppl 1998;83:2776-81.
7. Cantalejo M, Jmenes Cossio JA. The lymphedema in our country.Abstract XVI Congress I.S.L. Madrid September, 4 1997.
8. Statistiche della sanit. 1997;Annuario 10: 1997.
9. Campisi C, Michelini S. Lymphedema epidemiology in Italy. Lymphology 1998;31 Suppl:243-4.
10. Michelini S, Failla A, Moneta G. Iatrogenic secondare lymphedema. Eur J Lymphol 2000;8:25.
11. Witte C, Witte M. Lymphedema prevention. Eur J Lymph 1996;6:Sp.Co.I.
12. Olszewsky W. Studies on prevention of dermatolymphangioadenitis and progression of lymphedema after mastectomy and groin dissection. Eur J Lymph. 1996;6:Sp.Co. I.
13. ISL. Executive Commitee. The diagnosis and treatment of peripheral lymphedema. Consensus Document. Lymphology 1995;28:113- 7.
14. Kauffmann A. Profilaxis of lymphedema- possibilities and limits. Eur J Lymph 1996;6:Sp.Co. I.
15. Biassoni P, Campisi C. Isotopic lymphography in the diagnosis and follow up of lymphedemas treated by microsurgery. Progress Lymphol 1996;29 Suppl 1:101-5.
16. Pecking AP. Upper limb lymphedema frequency in patients treated by conservative therapy in breast cancer. Progress in Limphology XV. Lymph Suppl 1996; 1:293-7.
17. Campisi C, Michelini S. Prevention of lymphedema: Italian Statistical data and the present role of conservative non operative treatments. Eur J Lymph 1996;6:Sp.Co.I.
18. Gloviczki P, Wahner HW. Clinical Diagnosis and Evaluation of Lymphedema. Vase Surg 1995;143:1899-920.
19. Gasbarro V, Castaldi A, Viaggi R. Approccio Terapeutico pluridisciplinare del linfedema degli arti: protocollo terapeutico. Flebologia 1997;8:75-80.
20. Francis GE, Kinmonth JB, Rollinson E, Rotblat J, Taylor GW. Lymphatic circulation studied with radiactive plasma protein. Br Med J 1957; 1:133-7.
21. Kinmonth JB. Lymphangiography in man;a method of outlining lymphatic trunks at operation. Clin Sci 1952;11:13-20.
22. Bernas MJ, Witte CI, Witte MH for the ISL bExecutive Committee. The diagnosis and treatment of peripheral lymphedema. Lymphology 2001;34:84-91.
23. Kinmonth JB, Hurst PAE, Edwards JM, Rutt DL. Relief of lymph obstruction by use of a bridge of mesentery and ileum. Br J Surg 1978;65:829.
24. Bollinger A, Insering I, Franzeck UK, Jager K. Fluorescence microlymphography in various forms of primary lymphedema. In: Bollinger A editor. The initial lymphatics: new method and findings. Verlag Stuttgart: George Thieme;1985. p.1400-6;2180-9.
25. Allegra C, Bartolo M Jr, Sarcinella R. Morphological and fonctional characters of the cutaneous lymphatic in primary lymphedema.Eur J Lymph 1996;6:Sp.Co.I, 24.
26. Vettorello GF, Gasbarro V. L’ecotomografia dei tessuti molli degli arti inferiori nella diagnostica non invasiva dei linfedema. Minerva Angiol 1992;17:1-3.
27. Bruna J. Computer tomography and magnetic resonance imaging on enlarged extremity: differential diagnosis of lymphedema. In: Jamal S editor. Progress in Lymphology XVII. Lymphology 2000;33 Suppl: 109-12.
28. Pecking A, Cluzan R. Explorations du systeme lymphatique: epreuve au bleu, lymphographies directs, lymphoscintigraphies, autres methodes. Encycl Med Chir (Elsevier, Paris) Angeologie 1997;19-1130.
29. Bouchet JV, Richard C, Carpentier PH, Franco A. Rducation en pathologie lymphatique. EMC, Angiologie 1997;19-3660.
30. Casley-Smith JR, Casley-Smith JR. Hight-proteins edemas and Benzopyrones. Sidney and Baltimore: Lippincott;1968.
31. Agence du Medicament, Rapid Alert – Pharmacovigilance, 29 November and 23 december 1996 – Pharmaceuticals newsletter N. 10, October 1996.
32. Casley-Smith JR. Modem treatment for lymphedema. Adelaide (Aus): L.A.A. ed.; 1994.
33. Clodius L, Foldi M. Therapy for Lymphedema to day. Int Angiol 1984;3:207-13.
34. Oliva E, Sarcinella R. Effectiveness of the physical therapy in lymphedemas treatment. Eur J Lymph 1996;6:Sp. Co. I, 23.
35. Foldi M, Kubik S. Lymphologie. 3rd edition. Stuttgard: Gustav Fischer Verlag;1993.p.469-526.
36. Ko DS, Lerner R, Klose G, Cosimi AB. Effective treatment of lymphedema of the extremities. Arch Surg 1998;133:452-8.
37. Lerner R. Complete decongestive physiotherapy and the Lerner Lymphedema Services Academy of Lymphatic Studies (The Lerner School). Cancer 1998;83 Suppl 12:2861-3.
38. Cavezzi A, Jakubiak I. Lymphedema: pathophysiology, diagnosis and treatment of a difficult disease. Aust N Z J Phlebol 2001;5.
39. O’Donnel TF, Howrigan P. Diagnosis and management of lymphedema. In: Bell PRF, Jamieson CW, Rukley CV editors. Surgical Management of Vascular Disease. Philadelphia: WB Saunders;1992.p.1305-27.
40. Gloviczki P. Treatment of secondary lymphedema. In: Ernst CB, Stanley JC editors. Current Therapy in Vascular Surgery. 2nd ed. Philadelphia: BC Decker 1991.p.372-8.
41. Campisi C, Tosatti E, Casaccia M, Ieracitano V, Cordaro S, Padula P et al. Lymphatic microsurgery. Minerva Chir 1986:41:46.
42. Charles RH. Elephantiasis scroti. In: Latham A ed. A System of Treatment. London: Churchill, 1912;3.
43. Taylor GW Surgical management of primary lymphedema. Proc R Spc Med 1965:58:1024.
44. Thompson N, Wee JTK. Twenty years’ experience of the buried dermis flap operation in the treatment of chronic lymphedema of the extremities. Chir Plast (Berl) 1980;5:147.
45. Kinmonth JB. Primary lymphedema of the lower limb: response to discussion. Proc R Soc Med 1965;58:1931.
46. Homans J. The treatment of elephantiasis of the legs: a preliminary report. N Engl J Med 1936;215:1099.
47. Sinstrunk WE. Further experiences with the Kondoleon operation for elephantiasis. JAMA 1918;71: 800.
48. Gasbarro V, Cataldi A. Altre tecniche chirurgiche dell’arto superiore e dell’arto inferiore nel linfedema. In: Genovese G ed. Chirurgia delle vene e dei linfatici. Milano: Masson, 2003.p.270-3.
49. Zhu JK, Yu GZ, Liu JX, Pang SF, Lao ZG, Tang HY. Recent advances in microlymphatic surgery in China. Clin Orthop 1987;215:32.
50. Campisi C. Lymphedema: moderndiagnostic and therapeutic aspects. Int Angiol 1999;18:14-24.
51. Baumeister RG, Seifert J. Microsurgical lymph vessel transplantation for the treatment of lymphedema: Experimental and first clinical experiences. Lymphology 1981;14:90.
52. Goldsmith HS. Long term evaluation of omental transposition for chronic lymphedema. Ann Surg 1974; 180: 847.
53. O’Brien BMC, Shafiroff BB. Mycrolymphaticovenous and resectional surgery in obstructive lymphedema. Word J Surg 1979;3:3.
54. Casley Smith JR. Update cost efficacies of various therapies for lymphedema. Abstract XVI Congress I.S.L., Madrid 1997.
55. Bross F, Fldi E, Vanscheidt W. Augustin M. Psychosoziale Krankheits-belastungen und Lebensqualitat beim Lympedema. Phlebologie 1999;28:70-3.
56. Casley Smith JR. Discussion of the definition, diagnosis, and treatment of lymphedema. In: Casley-Smith JR, Piller NB. Progress in Lymphology. X edition. University of Adelaide Press, 1986.
57. Alliot F. Body Image and Rorscharch test in Lymphedema. XVI Congres ISL, Madrid 1997.
58. Orvidas LJ, Kasperbauer JL. Pediatric lymphangiomas of the head and neck. Ann Otol Rhinol Laryngol 2000:109:411-21.
59. Alqahtani A, Nguyen LT, Flageole H, Shaw K, Laberge JM. 25 years’ experience with lymphangiomas in children. J Pediatr Surg 1999;34:1164-8.
60. Papendieck CM. Lymphatic dysplasia in paediatrics. A new classification. Int Angiol 1999; 18:6-9.
61. Gallagher PG, Mahoney MJ, Gosche JR. Cystic hygroma in the fetus and newborn. Semin Perinatol 1999;23:341-56.
62. Fordham LA, Chung CJ, Donnelly LF. Imaging of Congenital Vascular and Lymphatic Anomalies of the Head and Neck. Neuroimaging Clin N Am 2000;10:117-36.
63. Fung K, Poenaru D, Soboleski DA, Kamal IM. Impact of magnetic resonance imaging on the surgical management of cystic hygromas. J Pediatr Surg 1998;33:839-41.
64. Ng JW, Wong MK. The difficulties and risks of surgical treatment of lymphangiomas in the cervicofacial region. J Pediatr Surg 1996;31:1463-4.
65. Molitch H, Unger EC, Witte L. Percutaneous sclerotherapy of lymphangiomas. Radiology 1995;194:343-7.
66. Stein M, Hsu RK, Schneider PD, Ruebner BH, Mina Y. Alcohol ablation of a mesenteric lymphangioma. J Vase Interv Radiol 2000; 11 (2 Pt 1):247-50.
67. Greinwald JH JR, Burke DK, Sato Y, Poust RI, Kimura K, Bauman NM et al. Treatment of lymphangiomas in children: an update of Picibanil (OK-432) sclerotherapy. Otolaryngol Head Neck Surg 1999;121:381-7.
Acknowledgements-We would like to acknowledge particular gratitude to Peter Gloviczki for his advice and for re-reading the manuscript.
Copyright Edizioni Minerva Medica Jun 2005