Venous-lymphatic disease: lymphoscintigraphic abnormalities in venous ulcers

Abstracts

Contexto: O sistema linfático tem papel relevante em qualquer tipo de edema periférico. Atualmente, a linfocintilografia é considerada o principal exame para diagnóstico da doença linfática das extremidades. Embora haja associação entre edema linfático e úlcera de estase venosa crônica, a fisiopatologia dessas alterações permanece indefinida. Objetivo: Verificar as alterações linfocintilográficas qualitativas que ocorrem em pacientes portadores de úlceras de estase dos membros inferiores. Métodos: Quarenta pacientes portadores de úlcera de estase venosa crônica ou cicatriz unilateral foram submetidos a linfocintilografia de ambos os membros inferiores. Foram estudados 25 mulheres e 15 homens, com média de idade de 53,7 anos (28 a 79 anos) e tempo médio de úlcera de 71,5 meses (3 a 240 meses). Foram comparados qualitativamente os parâmetros linfocintilográficos dos membros inferiores, previamente classificados em três grupos de acordo com a classificação clínica, etiológica, anatômica e patológica (CEAP): I, membros sem sinais clínicos de doença venosa ou com telangiectasias e veias reticulares (classes 0 e 1); II, membros inferiores com veias varicosas, edema e/ou alterações de pele e subcutâneo (classes 2, 3 e 4); III, membros inferiores com úlcera e/ou cicatriz (classes 5 e 6). Resultados: Quando foi comparada a presença de alterações linfocintilográficas dos membros com úlcera ou cicatriz (grupo III - classes 5 e 6) com as dos membros sem úlcera (grupos I e II - classes 0, 1, 2, 3 e 4), houve diferença significativa (p < 0,001). Estratificando os membros inferiores de acordo com a classificação CEAP, também foi observada diferença estatisticamente significante (p < 0,001), sendo as alterações linfocintilográficas presentes em 72,5% no grupo III (classes 5 e 6), 30,8% no grupo II (classes 2, 3 e 4) e 7,1% no grupo III (classes 0 e 1). Em relação aos parâmetros analisados na linfocintilografia, ocorreu diferença significativa entre o grupo III e os outros grupos quanto à retenção de radiofármaco, adenomegalia inguinal e refluxo dérmico. Não houve significância nos parâmetros linfonodo poplíteo e circulação colateral. Conclusão: Considerando os resultados, conclui-se que quanto mais grave a estase venosa crônica, maiores serão as alterações linfocintilográficas observadas, corroborando a associação entre doença venosa e linfática e entre linfedema secundário e estase venosa crônica.

Úlcera; estase venosa; linfocintilografia

ORIGINAL ARTICLE

Venous-lymphatic disease: lymphoscintigraphic abnormalities in venous ulcers

José Humberto Silva^I; Maria del Carmen Janeiro Perez^I; Newton de Barros Jr.^I; Mário Luiz Vieira Castiglioni^II; Neil Ferreira Novo^III; Fausto Miranda Jr.^I

^I

^IIRadioisotope Sector, Department of Imaging Diagnosis, UNIFESP-EPM, São Paulo, SP, Brazil

^IIIProfessor, Public Health, Universidade de Santo Amaro (UNISA), Santo Amaro, SP, Brazil

Correspondence

ABSTRACT

Background: The lymphatic system plays a relevant role in any type of peripheral edema. Lymphoscintigraphy is currently considered the primary test in the diagnosis of lymphatic disease of the lower limbs. Although there is an association between lymphatic edema and chronic venous ulcers, the physiopathology of such changes remains uncertain.

Objective: To assess qualitative lymphoscintigraphic findings in patients with chronic venous ulcers of the lower limbs.

Methods: Forty patients with unilateral chronic venous ulcer or scar were submitted to bilateral lymphoscintigraphy of the lower limbs. The sample was comprised of 25 women and 15 men, with a mean age of 53.7 years (28 to 79) and mean ulcer duration of 71.5 months (3 to 240 months). Lymphoscintigraphic parameters were qualitatively compared among three groups of lower limbs previously classified according to the clinical, etiologic, anatomic and pathologic classification (CEAP): I, limbs without clinical signs of venous disease or with telangiectasias and/or reticular veins (classes 0 and 1); II, limbs with varicose veins, edema and/or skin and subcutaneous alterations (classes 2, 3 and 4); III, lower limbs with ulcer and/or ulcer scars (classes 5 and 6).

Results: There was a significant difference (p < 0.001) in the comparison of lymphoscintigraphic findings of the lower limbs with (group III - classes 5 and 6) and without ulcers/scars (groups I and II - classes 0, 1, 2, 3 and 4). There was also a significant difference (p < 0.001) in the comparison of groups according to the clinical CEAP classification: lymphoscintigraphic abnormalities were present in 72.5% in group III (classes 5 and 6), in 30.8% in group II (classes 2, 3 and 4), and in 7.1% in group I (classes 0 and 1). There was a statistically significant difference between group III and the other groups with regard to radiotracer retention, inguinal adenomegaly and dermal reflux. There was no significance as to the parameters popliteal lymph node and collateral circulation.

Conclusion: The more severe the venous chronic stasis, the more lymphoscintigraphic abnormalities were observed, corroborating the association between venous and lymphatic disease and between chronic venous stasis and secondary lymphedema.

Keywords: Ulcer, venous stasis, lymphoscintigraphy.

Introduction

Chronic venous failure is defined as changes resulting from long-term venous hypertension, which occur in skin and subcutaneous cellular tissue due to valve insufficiency and/or venous obstruction. Venous valve failure and/or obstruction leads to increased venous pressure in veins, venules and venous capillaries (due to increase in hydrostatic pressure and permeability), distension of the capillary wall and increase in interendothelial pores, causing accumulation of higher-molecular-weight proteins in the tissue and increased tissue osmotic pressure.¹

The lymphatic system plays a major role in any type of peripheral edema,² and there is a close anatomical relation between veins and superficial lymphatics. In chronic renal failure, there may be insufficiency secondary to lymphatic drainage due to volumetric overload in lymphatics that were initially normal, which multiply their function to compensate the edema resulting from venous stasis. At the beginning of the process, there is increase in lymphatic flow for removal of protein excess and local fluid. When the offer exceeds the capacity of lymphatic vessels, increase in high-molecular-weight proteins and liquid in the tissues favors lymphangitis and erysipelas, which can cause thrombosis of lymphatic canaliculi and consequent progressive worsening of the edema and other complications, such as lipodermatosclerosis and stasis ulcer. When the patient had lymphedema secondary to chronic venous stasis, such patient has a venous lymphatic disease.³

Lymphoscintigraphy is currently considered as the main diagnostic examination for lymphatic disease of the limbs, reaching 90% sensitivity and 100% specificity.^4,5 However, there are few studies in the literature relating stasis ulcer with lymphatic lesion using lymphoscintigraphy.^6,7

The lack of standardization or the non-specification of analyzed parameters and the controversy as to the outcomes of such studies led to a qualitative assessment of lymphoscintigraphic changes in patients with unilateral chronic venous stasis, either open or healed, in the lower limbs, comparing them with possible changes found in contralateral limbs without ulcer. In addition, another objective of this study was to verify the correlation between changes found in the lymphoscintigraphic examination and severity of venous stasis clinically classified according to CEAP.⁸

Methods

A total of 40 patients were prospectively evaluated after being recruited from the vascular surgery outpatient of UNIFESP-EPM, with diagnosis of current or healed stasis ulcer in only one lower limb, from November 2002 to December 2003. The project was analyzed and approved by the Research Ethics Committee UNIFESP-EPM (no. 1002/02) and all patients signed a consent form.

The population was comprised of 25 women and 15 men, mean age of 53.7 years (28-79 years). All patients had current or healed unilateral venous stasis ulcer, with mean ulcer duration of 71.4 months (3-240 months). Patients with bilateral ulcer were excluded so that the limbs could be compared as to lymphoscintigraphic changes and also patients who had ulcers with signs of infection. Such patients were submitted to clinical examination, grouped according to CEAP classification and evaluated by bilateral lymphoscintigraphy of the lower limbs.

Group I included classes 0 and 1, with limbs without clinical signs of venous disease or with telangiectasias and/or reticular veins. Group II included classes 2, 3 and 4, patients with varicose veins, edema and/or skin or subcutaneous changes. Group III included classes 5 and 6, with changes in previous classes and open or healed ulcer.

Lymphoscintigraphy was performed by intradermal injection of Dextran 185 MBq (5 mCi) labeled with technetium^99m in the first interdigital space bilaterally. Images were acquired at 1 and 3 hours after injection.⁵

Qualitative analysis of lymphoscintigraphy was performed by independent observers experienced in nuclear medicine. Observers had no previous knowledge of the patients. To avoid any bias in parameter analysis, examinations were presented without identification and clinical history. Parameters analyzed bilaterally were presence of popliteal lymph node, radiopharmaceutical retention, presence of collateral circulation, inguinal adenomegaly and dermal reflux. Data were recorded in a specific protocol for each patient and submitted to statistical analysis.

Non-parametric tests were used for statistical analysis, considering the nature of variables:

- Cochran's G test,⁹ to analyze concomitances of varied lymphoscintigraphic changes. Such test was individually applied for lower limbs in all three groups.

- Chi-square test for 2 x 2 tables or 2 x n tables,⁹ with the aim of comparing groups with lymphoscintigraphic change and without lymphoscintigraphic change in relation to CEAP groups. The same analysis was applied to compare groups as to presence of popliteal lymph node, radiopharmaceutical retention, collateral circulation, inguinal adenomegaly and dermal reflux. Significance level was set in 0.05 or 5% in all tests.

Results

There was significant difference relative to presence of lymphoscintigraphic change in the lower limb between groups III and groups I and II, with changes in 72.50 and 22.50%, respectively (Table 1).

When changes found in the lymphoscintigraphic analysis of group III were compared, presence of dermal reflux, inguinal adenomegaly and radiopharmaceutical retention were more frequent, and presence of popliteal lymph node was less frequent. Such data were statistically significant (p < 0.001). As to lymphoscintigraphies performed in groups I and II in association, only radiopharmaceutical retention was more frequent, with statistical significance (p < 0.010). When changes between group III and groups I and II in association were compared, there was statistically significant difference in all parameters, except for collateral circulation (Table 2). There was interrater agreement > 80% in all parameters, and in the "collateral circulation" parameter there was higher number of disagreements, but with no statistical significance (p < 0.05%).

Table 2 - Click to enlarge

Analysis of presence of lymphoscintigraphic change in lower limbs according to the CEAP classification showed statistically significant difference (p = 0.000); lymphoscintigraphic change was more frequent in group III and less frequent in groups I and II (Table 3).

When lower limbs were assessed according to lymphoscintigraphic changes in relation to CEAP classification, there was statistically significant difference in radiopharmaceutical retention (Figures 1, 2, 3 and 4), inguinal adenomegaly (Figure 2) and dermal reflux (Figures 1 and 4) There was no statistically significant difference in terms of popliteal lymph node (Figure 2) and collateral circulation (Figure 3) (Table 4).

Discussion

Influence of venous diseases on the lymphatic system has been little studied, although there may be physiopathological and therapeutic implications. Both venous and lymphatic diseases can be manifested by edema, and differential diagnosis is not always simple, especially in the early stages of lymphedemas. There are reports in the literature indicating that lower limbs with chronic venous hypertension have increased lymphatic flow and that, according to lymphoscintigraphy, such increase may reach two to three times above the normal value.¹⁰

The literature is rich in studies on accuracy of lymphatic system assessment using lymphoscintigraphy for diagnosis, which is considered the initial method of choice to discard or confirm lymphatic lesions, since for qualitative assessment sensitivity ranges between 70-92% and specificity is 100%.^4,5 It is an objective, safe and fast examination that detects changes earlier and with few complications; in addition, it has low radiation and provides identifiable images of anatomic and functional changes of lymphatic vessels and lymph nodes, and can be easily repeated if necessary.^5,11-15 Dextran labeled with technetium^99m was used because the material can be easily obtained and data can be easily stored and due to the satisfactory quality of images, as has been standardized and published in previous studies.^{5,12-14,16-19} Analyzed parameters were presence of popliteal lymph node, which can be considered a sign of drainage failure by normal lymphatic pathways; dermal reflux, due to extravasation of radioisotope by hypertension in lymphatic collectors close to the ulcerated and/or healed lesion; inguinal adenomegaly, probably as a consequence of recurrent ulcer infections; radiopharmaceutical retention due to overload of lymphatic collectors caused by increased hydrostatic pressure and presence of collateral circulation. Collateral circulation is formed by a network of non-functional communications in the physiological state, and can become substitution pathways when the main lymphatic draining currents are saturated or blocked; in such case they are considered as non-usual pathways.²⁰

With regard to the main lymphoscintigraphic changes found in limbs with ulcer (popliteal lymph node, radiopharmaceutical retention, dermal reflux and inguinal adenomegaly) and in limbs without ulcer (radiopharmaceutical retention), this study found results similar to those reported by other authors,^21,22 which showed morphological changes in superficial lymphatic vessels in dermatosclerosis areas, suggesting that local infections and periulcer fibrosis cause lesions of the superficial lymphatic vessels, leading to dermal reflux and radiopharmaceutical retention.

Another study on lymphatic function, evaluated by quantitative analysis, showed that lymphatic function was reduced in ulcerated limbs in comparison to normal limbs, in addition to reduced lymphatic drainage with age in control individuals older than 65 years.⁷ This suggests that increased age deteriorates the intrinsic function of the lymphatic pump and the transportation ability of the lymphatic system.²³

Many authors described changes in direct lymphographies performed in patients with deep venous thrombosis, varicose disease of the lower limbs with chronic edema and post-thrombotic syndrome, showing lymphatic vessels a little larger, more dilated and tortuous (rosary beads) and more lymph nodes that are earlier contrasted in relation to the normal limb.^24-26 Patients with ulcers secondary to chronic venous hypertension also had dilatations and tortuosities of collecting vessels, contrast extravasation at the ulcer site and contrast flow through the skin, without opacification of collecting vessels. The aspect was compatible with diagnosis of lymphedema and similar to that of lymphoscintigraphies²⁷ in relation to dermal reflux in the limb and to concentration of radiopharmaceutical at the ulcer site, also observed in the present study.

Use of lymphoscintigraphy in patients with edema secondary to venous obstructions (venous, femoral or popliteal thrombosis), congestive heart failure and hypoproteinemia showed increased velocity of radiopharmaceutical removal.²⁸ Other studies did not show uniform patterns of lymphatic flow.²⁹ Results were as follows: the earlier the diagnosis of venous disease, the more accelerated the lymphatic flow;³⁰ reduction in radiopharmaceutical, similar to what is found in patients with primary lymphedemas;³¹ extensive lymphatic destruction in the affected region and consequent reduction in lymphatic flow;³² and reduced lymphatic transportation in deep lymphatic vessels and increased lymphatic transportation in superficial lymphatic vessels in the early stage,³³ but reduced in case of stasis ulcer and/or recurrent lymphangitis.⁶ As the disease and its complications (recurrent skin ulcers) progress, lymphatic flow and consequent lymphatic transportation decreases,^3,34 and is slow in patients with venous insufficiency. Such result is in disagreement with a previous study that showed increased inguinal flow in limbs with venous edema, compared with normal limbs.¹⁰ Such difference in lymphatic transportation of venous insufficiency can be explained by edema duration. In acute venous thrombosis or at the early stage of chronic venous failure, there is increase in capillary filtration and a faster transportation in normal lymphatic channels.³⁵ Afterward, with constant lesion of lymphatic capillary vessels in the subcutaneous by infection and local fibrosis, the lymphatic transportation ability is compromised, and an edema occurs in the limb.^3,32

There are no studies in the literature qualitatively assessing lymphoscintigraphic changes in patients with unilateral stasis ulcers, classified according to CEAP that can be compared with the results from this study. Therefore, it can be concluded that the most frequent lymphoscintigraphic changes found in this study in limbs with ulcers are a result of the skin lesion itself and caused by duration of chronic venous stasis. Based on the available evidence, the hypothesis is that lymphatic channels do not play a major role in the early stage of venous stasis, but are affected by overload, leading to changes in capillary vessels and interstitial fluid and, from then on, contribute as a secondary factor to deterioration of skin and subcutaneous tissue. Lymphatic lesion is an important component in persistent chronic venous ulcer and can explain the difficulty of an efficacious treatment of complex leg ulcers.

References

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Correspondência:

Maria del Carmen Janeiro Perez

Rua Borges Lagoa, 710/14, Vila Clementino

CEP 04038-031 - São Paulo, SP

Tel.: [phone]

Fax: [phone]

Publication Dates

• Publication in this collection
  26 May 2009
• Date of issue
  Mar 2009

History

• Accepted
  15 Nov 2008
• Received
  27 Aug 2008