LYMPHEDEMA

SURGERY AND MICROSURGERY FOR THE TREATMENT OF LYMPHEDEMA SINCE 1973

According to data from the international literature, which correspond to those published by the World Health Organization, lymphedema has a worldwide incidence of 300 million cases (approximately one in every 20 people). Almost half of lymphedemas are of primary origin, due to congenital lymphangio-adeno-dysplasia; that is, due to a congenital malformation and subsequent poor functioning of lymph nodes and/or lymphatic vessels. Some 70 million cases are of parasitic origin (the most common forms are caused by Filaria Bancrofti), especially in tropical and subtropical regions (India, Brazil, South-Africa). Other 50 million are post-surgery cases, mostly following breast cancer surgery. The remaining 30 million cases are generally caused by functional problems related to water overload on lymphatic circulation (and, in particular, following deep venous thrombosis of the lower limb, liver failure, nephrostic syndrome, arteriovenous fistulas).

In particular, with regard to secondary lymphedema, the incidence of lymphedema of the upper limb in women who have undergone mastectomy or quadrantectomy with axillary lymphadenectomy, amounts to 20-25%, and up to 35-40% when combined with radiation therapy. When the sentinel node approach is followed, secondary lymphedema incidence ranges between 3% and 22%. As to lymphedema of the lower limbs secondary to gynaecological or urological cancer treatment, the incidence ranges between 5% and 30%. Due to the high incidence of secondary lymphedema, the importance of lymphostatic disease prevention should be pointed out, in terms of early diagnosis and treatment. Women are more affected than men, and the age group in their 3rd-4th decade is the most often affected.

The incidence of more or less clinically overt lymphangitis, as a complication of lymphostasis, and sufficiently severe to require slow-release antibiotic treatment, for both therapeutic and prophylactic purposes, is very high (practically present in almost all cases).

Lymphedema is a not so rare clinical condition featuring a slowdown or block of lymphatic circulation in the affected limb/s, with progressively more severe evolution and onset of recurrent complications, such as acute erysipeloid lymphangitis, which accounts for a fast increase in edema volume and thickness. Although pathogenic details are still an open issue, the basic principles of physiopathology are well known. On one hand, the basic lymphatic dysfunction may consist of a low output failure of the lymphatic system: that is, a general reduction in lymph transport. This type of dysfunction may be caused by either congenital lymphatic dysplasia – primary lymphedema – or by anatomic obliteration, following radical surgery resection (for example after axillary, iliac-inguinal, or retroperitoneal lymph node resection), following repeated bouts of lymphangitis with lymphangiosclerosis, or resulting from functional failure (for example, lymphangiospasm, valvular paralysis and insufficiency) – secondary lymphedema. However, the common feature is the fact that lymph transport falls below the level needed to handle the microvascular filtration load, which includes plasma and cell proteins, that normally enter the interstitium from blood circulation. On the other hand, lymphatic circulation high output failure occurs when a standard or increased output is overwhelmed by an excessive load of capillary blood filtration products: for example, in the case of liver cirrhosis (ascites), nephrotic syndrome (anasarca), and deep venous insufficiency of the lower limbs (post-thrombophlebitic syndrome). Failure to keep lymphedema in check may lead to repeated infections (dermato-lymphangioadenites – DLA), progressive trophic pachydermatous skin dysfunctions, and, in rare cases, even to the development of angiosarcoma, a highly lethal disease (Steward-Treves syndrome).

Lymphedemas are generally distinguished into primary or congenital and acquired or secondary.

Primary lymphedemas are further grouped into connatal, namely already present at birth, with early onset – if they are observed before 35 years of age – or late onset, if they develop after 35 years of age. Connatal primary lymphedemas include sporadic forms, that can be distinguished from inherited-familial forms and which, in the majority of cases, can be considered to be part of more or less complex malformation syndromes, either correlated or not to specific gene anomalies. In order to identify the type of dysplasia underlying the various forms of congenital lymphedema, C. Papendieck’s classification is applied: LAD I (lymphangiodysplasia – dysplasia of lymphatic vessels), LAD II (lymphadenodysplasia – lymph node dysplasia), LAAD (lymphangioadenodysplasia – dysplasia of lymphatic vessels and lymph nodes). The term dysplasia includes: agenesis, hypoplasia, hyperplasia, fibrosis, lymphangiomatosis, hemartomatosis, and valvular insufficiency.

Secondary lymphedemas can be distinguished into post-surgical, post-actinic, post-traumatic, post-lymphangitis, and parasitic.

Lymphedema Classification

Primary or congenital

  • Connatal (already present at birth)
  • Sporadic
  • Hereditary -familial
  • Early (with onset before 35 years of age)
  • Late (with onset after 35 years of age)

Secondary or acquired

  • Post-surgical
  • Post-actinic
  • Post-traumatic
  • Post-lymphangitis
  • Parasitic

Generally speaking, a three-stage system is applied to stage lymphedemas, even if the 2nd and 3rd stage can be further carved up in two sub-stages, thus leading to a 5-stage classification.

Staging of Lymphedemas

Stage 1:

a) No edema, but the presence of lymphatic impairment (for example, following mastectomy with axillary lymphadenectomy, with equal extremities in terms of volume and thickness).

b) Mild edema reversible with limb elevation and night rest.

Stage 2: Persisting edema, with only partial regression with limb elevation and night rest.

Stage 3: Persisting edema (no spontaneous regression with limb elevation) and progressing disease (acute erysipeloid lymphangitis).

Stage 4: Fibrolymphedema (initial lymphostatic verrucosis) with “column-shaped” limb.

Stage 5: Elephantiasis with severe deformation of the affected extremity, marked and extended, sclerodermic pachidermitis and lymphostatic verrucosis.

The above staging includes both primary and secondary lymphedemas, clinically overt and sub-clinical lymphedemas (Stage IA), in which a lymphoscintigraphy allows the detection of any initial lymphatic flow impairment, and the likely disease progression, irrespective of lymphedema nature. The staging of lymphedema is based on clinical and diagnostic-instrumental criteria: type of edema, clinical progression of disease during the day and with decubitus, number and severity of lymphangitic complications, edema thickness, and disease-related skin anomalies.

Finally, it is possible to assess the severity of the clinical picture based on the volume difference between the affected and non-affected limb: such difference can be defined as minimum (<20% in volume increase), moderate (from 20 to 40% increase), and severe (> 40 increase).

This staging has recently been updated (see International Congresses of Monte Carlo and Sydney), and aligned with the staging in three stages of the International Society of Lymphology (as described in the presentation).

In the majority of patients, lymphedema can be diagnosed based on clinical history and physical examination: generalized edema with increased thickness, depending on its higher or lower fibrosclerotic tissue component, no pitting, even in the earliest stages of the disease, positive Stemmer sign (e.g. lack of skin plication at the root of the second toe), dystrophic skin lesions (post-lymphangitic sequelae, hyperkeratosis lymphostatic verrucosis, lymphorrhoea, chylorrhea), frequent dermato-lymphangioadenitis (DLA) complications. Further, lymph node examination is also useful to detect any associated acute or chronic lymphadenopathy.

In more complex forms of angiodysplasia, featuring arteriovenous hyperstomy (Mayall Syndrome) or congenital arteriovenous macro and microfistulas (Klippel- Trenaunay or Klippel-Trenaunay-Servelle Syndrome), the clinical picture may feature the following: gigantism with elongation of the extremities, more or less marked foot dysmorphism, flat or map-like Port-wine stain angiomas, hyperhydrosis of the plantar surface of the foot. However, there are also spurious forms, which are more difficult to diagnose, owing to prevailing lymphedematous components.

Also, in some patients, confounding conditions such as morbid obesity, venous insufficiency, occult trauma, and repeated infections may complicate the clinical picture. Moreover, in considering the basis of unilateral or bilateral extremity lymphedema, especially in adults, an occult tumor needs to be considered. For these reasons, a thorough and integrated medical evaluation is indispensable before embarking on lymphedema treatment. Co-morbid conditions such as congestive heart failure, hypertension, and cerebrovascular disease including stroke may also influence the therapeutic approach undertaken.

If the diagnosis of lymphedema is unclear or in need of better definition for prognostic considerations, consultation with a clinical lymphologist or referral to a lymphologic center is recommended.

Lymphangioscintigraphy is the first choice of test for edema diagnosis, in order to confirm the nature of lymph stasis and to identify its cause (either obstacle or reflux), to evaluate the extension of disease (dermal back flow), any higher or lower damage to deep vs. surface lymphatic circulation, and drainage through lymph nodes. Therefore, the study of both the deep and surface lymph circulation is useful, by proper tracer injection into specific drainage sites of both systems. This is a non-invasive, easily repeatable procedure, even in newborn babies. With this imaging technique, even stage IA – not yet clinically manifest – lymph stasis can be detected, thus playing a fundamental role in secondary lymphedema prevention. This investigation technique is also useful in following up on the outcome of various lymphedema treatments and, in particular, of lymphatic microsurgery.

Lymphography is a modern investigation technique, which is essential when studying complex congenital or acquired conditions of chyliferous vessels, the cisterna chyli, and the thoracic duct. In the most modern facilities, it is performed in the operating room, under local anesthesia, with microsurgical preparation of the lymphatics.

Ultrasonography, CT, and MRI are useful diagnostic tools to define complex syndromes featuring angiodysplasia and lymphedema combinations, as well as to investigate the organic obstructive origin, if any, of lymphedema secondary to a tumor. Lymphangio-MRI, in particular, using the fatty-tissue subtraction technique, provides useful information in advanced obstructive lymphedema conditions, featuring dilated lymphatics swollen with lymph.

Investigations of venous circulation with Color-Doppler Ultrasound – commonly employed for the instrumental assessment of an edematous limb -, Phleboscintigraphy, and Phlebography (if required, based on the Ultrasound examination outcome) are essential. Investigations of arterial circulation may also become necessary in panangiodysplasia conditions associated with lymphedema. In all these cases, in addition to Color-Doppler Ultrasound, digital arteriography may also be useful.

Indirect Lymphography, Fluorescent Microlymphography, Houdack – McMaster Lymphochromic Test, flow and lymph pressure measurement, as well as Laser Doppler may all provide useful information on the anatomic and functional conditions of blood microcirculation (Laser Doppler), as well as of the initial lymphatics and lymphatic collectors. However, their clinical use is limited.

Diagnostics of lymphedemas

Main investigations

  • Lymphoscintigraphy
  • Lymphography and lymphangio-CT
  • Lymphangio-MR
  • Color-Doppler ultrasound

Additional investigations

  • Laser-Doppler
  • Fluorescent Microlymphography
  • Indirect Lymphography
  • Houdack-Mc Master Lymphochromic Test
  • Phleboscintigraphy
  • Phlebography
  • Digital Arteriography

 

Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema
Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema
Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema
Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema

Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema

Figure 1,A-B Multiple End-to-end Lymphatic – Venous Anastomosis–with telescopic technique, following anastomosis of lymphatic collectors into the venous segment.

Figure 2 Derivative lymphatic-venous microsurgery in brachial region for the treatment of upper limb lymphedema (the median nerve and the brachial artery can be seen).

End-to-side Lymphatic – Venous Anastomosis is best performed with Degni’s grooved needle. The lower flap of the lymphatic segment wall is put inside the vein with an end-to-side arrangement, thus acting as a valve to prevent blood reflux into the lymphatic collector. This technique was later modified (Campisi, 1989), by using the outlet of a collateral vein of the major vein as venous access for lymphatic collectors. With this technical expedient – owing to smooth muscle cells arrangement in the venous wall at the point of entry of lymphatic collectors –, there is no risk of stenosis of the anastomosis.

With reconstructive microsurgery techniques, the lymphatic flow is resumed by overcoming the obstruction site, through the implant of autologous or venous segments between collectors down and upstream the obstruction:

  1. Lymphatic-Lymphatic Anastomosis (LLA)
  2. Segmental Lymphatic Vessel Autotransplantation (SLAT)
  3. Lymphatic-Venous-Lymphatic-Plasty or Lymphatic-Venous-Lymphatic Anastomosis (LVLA).
  4. Free Lymphatic- Lymph Nodal Flaps (FLF)

Lymphatic-lymphatic anastomosis is rarely employed, because the gap between afferent and efferent collectors is often too wide to fashion a direct anastomosis. Hence, the interposition of a lymphatic segment or a vein is often required. Lymphatic collector self-transplantation is a time-consuming technique, which allows only 1 or 2 lymphatic pathways of the affected extremity to be reconstructed. It can be applied exclusively in the treatment of monolateral lymphedemas, since the lymphatic segment is harvested from the healthy side, with a surgical resection, which, being relatively extensive, could in turn be the cause of iatrogenic lymphedema. The interposition of autologous venous grafts between lymphatic collectors upstream the lymphatic flow obstacle is another, easy to perform method, alternative to derivative microsurgery (Campisi, 1982).

Venous grafts are easily harvested from the same site of surgery, from the volar surface of the forearm or the leg (collateral branches of the saphena veins), with a length from 7 to 25 cm and a gauge of 1.5-5 mm. This method is mostly used for the lower limbs. The site of operation is the supra or sub-inguinal region; a telescopic anastomosis is fashioned, with a U stitch in non-resaborbable nylon, monofilament, 8/0 material. A Lymphatic-Venous-Lymphatic Anastomosis (LVLA) takes 2 and a half hours on average to complete, and it is normally applied in cases of venous disease (e.g. venous hypertension, valvular insufficiency) that cannot be surgically treated (Figure 3).

Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema

Figure 3, A-C: Schematic drawing and intra-operative phases of a reconstructive Lymphatic-Venous-Lymphatic Microsurgery, with interposition of autologous venous segment between lymphatic collectors downstream and upstream the obstacle.

In cases of severe lymphatic-lymph node hypoplasia, free lymphatic-lymph node flaps can offer a good solution, featuring a free microvascular self-transplantation of lymphatic-lymph node tissue in the axillary or inguinal region of the affected extremity.

Microsurgical Techniques for lymphostasis treatment boast a good success rate, with 50% to 75%, and up to 100% reduction in edema thickness and volume in the affected extremity from pre-treatment conditions, depending on disease stage: the earlier the treatment, the higher the percentage in edema regression. Stable and long-lasting results have been reported in follow-up studies after 15 years from surgery of patients treated for limb lymphedema with Lymphatic Microsurgery. Treatment outcome is assessed based on water volumetry and lymphatic scintigraphy performed before treatment and at various intervals from surgery.

Medium and long term outcome assessment

Treatment outcome is assessed with volumetry and lymphatic scintigraphy. As to volume measurement of the affected extremity, a water volumeter is employed, featuring a cylinder with known surface size, filled with water, and communicating with a graduated column in transparent material, where the limb is introduced. Volume changes of the limb are measured against the amount of displaced water. In cases of lymphedema affecting only one extremity, the measurements are compared to the healthy limb. Alternatively, the truncated cone formula can be applied and the limb volume measured by taking the limb circumference.

With lymphatic scintigraphy (Figure 4), performed at various intervals from surgery, the patency of derivative or reconstructive microsurgical anastomoses can be assessed by 1) showing dermal backflow reduction, 2) tracer disappearance at the level of the micro-anastomoses due to blood flow, 3) early liver “uptake” of the tracer, which is indicative of a faster flow of tracer into systemic circulation, 4) resumption of preferential lymphatic pathways with tracer upflow, 5) display of the interposed venous segment.

Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema   Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema

Figure 4: Lymphoscintigraphy before and after derivative lymphatic-venous microsurgery – in 1/3 midportion of the forearm volar surface. Development of a preferential lymphatic drainage pathway can be observed, together with dermal back flow reduction, and early liver uptake of tracer.

Microsurgical techniques are highly beneficial especially in the early stages of disease: through the resumption of preferential lymph flow pathways in the affected extremity, good results (even healing) can be achieved with Microsurgery. (Figures 5-14). However, even in more advanced cases, microsurgical techniques lead to quick and significant edema reduction (in terms of liquid component), which is maintained over time and even improved with medical-physical procedures, aimed at maximum performance of surgically fashioned drainage pathways.

Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema      Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema      Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema      Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema      Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema      Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema   Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema         Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema   Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema

Figure 5: 3rd stage upper limb lymphedema, secondary to breast cancer treatment, before and after microsurgery.
Figure 6: 3rd stage lower limb primary lymphedema, before and after derivative lymphatic-venous microsurgery.
Figure 7: Congenital, 4th stage lymphedema of the lower limbs, caused by gravitational reflux, in a child, before and one week after bilateral derivative lymphatic-venous microsurgery in the inguinal-crural region.

Figure 8: 3rd stage upper limb lymphedema, post-mastectomy, before and long-term stable results after microsurgery

Figure 9: 3rd stage lower limb lymphedema, secondary to cancer treatment, before and after microsurgery

Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema

Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema     Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema

Figure 5: 3rd stage upper limb lymphedema, secondary to breast cancer treatment, before and after microsurgery.
Figure 6: 3rd stage lower limb primary lymphedema, before and after derivative lymphatic-venous microsurgery.
Figure 7: Congenital, 4th stage lymphedema of the lower limbs, caused by gravitational reflux, in a child, before and one week after bilateral derivative lymphatic-venous microsurgery in the inguinal-crural region.

Figure 8: 3rd stage upper limb lymphedema, post-mastectomy, before and long-term stable results after microsurgery

Figure 9: 3rd stage lower limb lymphedema, secondary to cancer treatment, before and after microsurgery

Lymphedema  sporadic lymphedema lymphoedema at birth lymphedema connatali lymphedema late lymphedema hereditary lymphoedema hepedic-familial lymphoedema early lymphedema

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