Evaluation of lymphatic compensation by lymphoscintigraphy in the postoperative period of breast cancer surgery with axillary dissection

REVIEW ARTICLE

Evaluation of lymphatic compensation by lymphoscintigraphy in the postoperative period of breast cancer surgery with axillary dissection

Laura Ferreira de Rezende^I; Felipe Villela Pedras^II; Celso Dario Ramos^III; Maria Salete Costa Gurgel^IV

^IPhD. Physical therapist, Department of Obstetrics and Gynecology, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.

^IIPhysician. Nuclear Medicine Service, Department of Radiology, Faculdade de Ciências Médicas, UNICAMP, Campinas, SP, Brazil.

^IIIPhD. Nuclear Medicine Service, Department of Radiology, Faculdade de Ciências Médicas, UNICAMP, Campinas, SP, Brazil.

^IVPhD. Department of Obstetrics and Gynecology, Faculdade de Ciências Médicas, UNICAMP, Campinas, SP, Brazil.

Abstract

The lymphatic system is a component of the human body that is closely related to the venous system. However, scientific knowledge of this system is limited. The etiology and risk factors for the development of postoperative lymphedema in patients with breast cancer seem to be multifactorial and have not been fully understood yet. The objective of this review of the literature was to describe lymphoscintigraphic pattern and to evaluate upper limb lymphatic compensation following breast cancer surgery with axillary dissection.

Keywords: Lymphatic system, lymphatic drainage, axillary dissection, lymphoscintigraphy, breast cancer.

RESUMO

O sistema linfático é um componente do corpo humano intimamente relacionado ao sistema venoso. Entretanto, o conhecimento científico a seu respeito é limitado. A etiologia e os fatores de risco para o desenvolvimento do linfedema no pós-operatório de câncer de mama são multifatoriais e ainda não foram completamente esclarecidos. O objetivo desta revisão da literatura foi descrever o padrão linfocintilográfico e avaliar as compensações linfáticas do membro superior no pós-operatório de câncer de mama com dissecção axilar.

Palavras-chave: Sistema linfático, drenagem linfática, dissecção axilar, linfocintilografia, câncer de mama.

Introduction

Breast cancer has high and significant mortality rates in women; it is the second most frequent type of cancer worldwide and the most common in the female population. In Brazil 49,400 new cases are expected for 2008, with raw estimated rate of 51 cases for each 100,000 women.¹

According to the American Cancer Society, there are now between 1 and 2 million breast cancer survivors in the USA, and about 15-20% of them have daily discomfort or disability in their upper limbs. It is estimated that between 120,000 and 600,000 patients suffer some type of postoperative complication.²

Upper limb edema ipsilateral to the breast submitted to surgery, complication with variable onset time between 2 and 92 months, mean of 14 months,^3,4 has incidence of 24-49% after mastectomy, 4-28% after tumorectomy with axillary dissection⁵ and 34% after surgery combined with radiotherapy,⁶ causing a substantial functional and psychological impairment for the patient.

Lymphedema is the most common postoperative complication, and its adverse effects directly affect the patient's quality of life. Although its incidence has been reduced due to early diagnosis and progress in therapeutic strategies, especially the technique of sentinel lymph node biopsy, lymphedema remains as a significant challenge for patients and physical therapists.² Szuba et al.⁷ believe that, despite these advances, increased incidence of breast cancer and increased survival of patients will lead to an increased incidence of lymphedema.

Lymphedema is a chronic, progressive and usually incurable disease. The increase in limb volume may deform the body image, as well as increase the patient's physical and psychological morbidity, in addition to causing significant impairment in function.⁵ It is a hard-to-treat change, and continuous search for better results does not justify existence of dissatisfactory treatments, although these results do not often have ideal responses meeting the expectations of patients and their physical therapists.⁸

Etiology and risk factors for the development of lymphedema in patients submitted to breast cancer surgery can be multifactorial and still not completely understood. Risk for lymphedema occurrence is associated with axillary dissection and radiotherapy, extension of surgical technique, infection,^5,9 age, number of dissected lymph nodes, number of positive lymph nodes and level of lymph node removal.¹⁰

Axillary dissection, due to absence of lymph nodes or only with presence of remaining lymph nodes, lead to a reduced ability of lymph transport from a lymphatic vascular system with intact tributaries, i.e., there will be a reduction in lymph transport in the arm and upper quadrant of the trunk.¹¹

The lymphatic system has several important functions. Among them are the control of macromolecular homeostasis, absorption of lipids, metastases, immunological function, and control of tissue fluids.¹² Its main characteristic is the ability to remove liquids and proteins from interstitial spaces. Removal of such elements, in turn, is only possible through a lymphatic capillary membrane, which is more permeable than the blood capillary membrane. Therefore, lymphedema may occur when there is failure in the lymphatic system, associated with inadequate action of macrophages and consequent stagnation of plasmatic proteins.¹³

After axillary dissection, the lymphatic system will search for compensation mechanisms as an attempt to supply absence of removed lymph nodes, adjusting the ability of lymph transport. These compensation mechanisms can be performed as follows:¹¹

- The intact lymphatic vessels that remained from surgery and radiotherapy start their valve functions;

- There is activity of collateral lymphatic flows with axillo-axillary and axillo-inguinal anastomoses;

- Protein-rich tissues migrate outside the area of lymphatic stasis through channels of connective tissue toward the boundaries of the upper quadrant of the trunk, resulting in healthy lymphatic vessels;

- Lympho-lymphatic anastomoses are developed in the area of axillary resection;

- Peripheral lympho-venous anastomoses can stabilize the ability of lymph transport through new connections between veins and lymphatics;

- Macrophages coming from the highest possible number of blood capillaries in the region of lymphatic stasis start protein lysis with the aim of stagnating concentration of plasmatic proteins.

In a study of a cadaver of an 81-year-old woman with history of mastectomy with right axillary dissection for 11 years, there was complete absence of superficial lymphatic paths in the right arm and close to the elbow, in addition to fibrosis and block of lymphatic channels. Many forms of lymphatic compensation were identified: dermal reflux; superficial lympho-lymphatic anastomoses; superficial and deep lympho-lymphatic anastomoses; lymphatic vessel atrophy, meaning block; and lympho-venous anastomoses.¹⁴

Lymphedema is a quantitative problem between produced lymphatic flow and transport ability. If the compensation mechanisms are insufficient, the balance between production and transport is ruined; if the normal production of lymph is higher than the transport ability, the lymphedema will immediately occur.¹¹

When a lymph node is resected, there is a process of lymphangiogenesis and, in many cases, the transport ability of new formed vessels seems to be sufficient to prevent clinical manifestation of the edema. The issue is knowing whether the normal parameters follow this process. Such response can be important, and it is possible to assume that any subtle change in lymphatic transport can change the tissue lymphatic drainage and, consequently, increase risk of lymphedema development.¹⁵

In an experimental study on animals, it was possible to observe that after lymph node removal in a period of 4 weeks there was occurrence of a plexus of small vessels as a gapped connection bridge between the prenodal duct and the prenodal vessels, with no clinical evidence of edema in the animal limb, suggesting that superficial lymphatic drainage had been restored. However, these bridges had very irregular structures, which created an increase in lymphatic flow resistance, causing a nonlinear relation between perfusion flow and pressure. It can also be noted that such structures were entangled in the fibrous tissue, distorting the lymphatic vessel path and contributing to an increase in flow resistance. Therefore, although the removed lymph node causes formation of new lymphatic vessels, there was an impairment in lymph transport flow.¹⁵

Regeneration of interrupted lymphatic vessels by lympho-lymphatic anastomoses is sensitive to altered healing formation, postoperative seroma, radiotherapy, and early improper exercises for shoulder rehabilitation,¹¹ representing impairment factors to this neoformation process. Less damaged tissues in less aggressive surgeries allow for new lympho-lymphatic connections.¹⁶

Restoration of lymphatic flow is benefited by good tissue healing, immobilization of the shoulder ipsilateral to the surgery, manual lymphatic drainage, and muscle contraction.^11,12,16

Lymphoscintigraphy

Lymphoscintigraphy is currently supported as the main diagnostic test for the peripheral lymphatic system, allowing for visualization of lymphatic vessels and lymph nodes, as well as quantification of lymphatic transport. Abnormal flows of the lymphatic system are lack of migration and slowness in radiopharmaceutical agents, opposite fluid flow into the skin, non-visualization of lymphatic vessels in the affected side, and absence or poor visualization of remaining and/or detectable lymph nodes.^17,18

Lymphoscintigraphy has clinical application to indicate and quantify lymphatic drainage from the morphological and functional perspectives, determine the number of sentinel lymph nodes and identify risk patients for development of lymphedema after lymph node dissection.⁷ It is a reliable method to measure lymphatic flow under uncertain conditions of increase or reduction in these activities.^19,20 Visual interpretation of the lymphoscintigraphic image associated with time of radiopharmaceutical appearance at the lymph node region provides reliable information on the normality or not of the lymphatic system, with specificity of 100% and sensitivity of 92-97%.^17,21 For image analysis the characteristics of distribution of the particles seen during lymphoscintigraphy are studied, considering accumulation of radiopharmaceutical agent in the tissue, presence of dermal reflux, lymphangiectasia, interruption of lymphatic vessels, and delayed transport as signs of lymphedema presence.^22,23

The lymphoscintigraphy protocol is not standardized and varies according to the diagnostic service. Differences include choice of radiopharmaceutical agent, type and location of injection, use of static or dynamic evaluations, and number and time between such evaluations.²²

The first radiopharmaceutical agent approved by the Food and Drug Administration (FDA), which is no longer used, was a small-sized colloid (3-30 nm), labeled with ^99mTc-pertechnetate. After came the ^99mTc-sulfur colloid (10-1,000 nm), which can be filtrated to remove large particles, creating a uniform particle size (10-50 nm).²²

Another frequently used microcolloid is albumin, a homogeneously sized particle (95% smaller than 80 nm) and easy to be labeled. It is quickly seen after injection, painless for the patient and proper for quantitative studies. Use of particles such as ^99mTc-labeled human serum albumin, dextran and human immunoglobulin has also been described. These can be seen by lymphoscintigraphy by two mechanisms, reabsorption and transport of the particle into the lymphatic capillary.²² In Brazil dextran (6-7 nm) is the most widely used, and is adequate for diagnosing lymphedema. All radiopharmaceutical agents are ^99mTc-labeled.

Dextran is a radiopharmaceutical agent soluble in the lymph, and has sufficiently large particles not to penetrate through the blood capillary membrane after injection in the interstitium. Glomerular filtration and urinary excretion occur when the dextran weighs less than 40 kDa after injection in the interstitium.²⁴

The technique of radiopharmaceutical injection to perform lymphoscintigraphy is another discussed issue. To study lymphatic extravasation, subcutaneous injection is better than intradermal injection. Subcutaneous or intradermal accesses can be used for studies of lymphatic surface in extremities.²²

Interpretation of lymphoscintigraphic images is better performed based on the recognition of abnormal distribution of the radiopharmaceutical agent and on knowledge of the relative time it takes to reach regional lymph nodes.¹⁷ Bourgeois et al.,¹⁹ for lymphoscintigraphy parameters, recommend use of the time the radiopharmaceutical agent takes to reach axillary lymph nodes, and Szuba et al.⁷ prefer amount of radiopharmaceutical accumulation in axillary lymph nodes.

Cambria et al.²⁵ proposed evaluation of lymphatic transport using dynamic lymphoscintigraphy by analysis of time of radiopharmaceutical agent appearance in the lymph node. This scale also considered the transport of lymphatic movement, distribution of lymphatic paths, visualization of lymph nodes and lymphatic vessels.

O’Mahony et al.²⁶ proposed a classification according to image quality, following the definition of lymphatic vessels as very poor, poor, adequate, good, and excellent. Szuba et al.²⁷ developed an empirical scale of static lymphoscintigraphy to visualize axillary lymph nodes, considering visible and symmetric lymph nodes as the normal pattern and non-visible lymph nodes as worse abnormality. Gloviczki et al.²¹ classified time of radiopharmaceutical appearance in lymph nodes combined with degree of visualization as clearly visible, little visible and not visible.

Lymphoscintigraphic study is considered as normal if discrete lymphatic channels drain the limb extremity and if regional lymph nodes are seen in up to 1 hour. A similar time is considered as normal lymphoscintigraphic study for the arrival of the radiopharmaceutical agent in the liver.²⁸ O’Mahony et al.²⁶ and Scarbrook et al.²³ considered 30 minutes as the normal time of radiopharmaceutical arrival in regional lymph nodes. The liver image can be seen when the radiopharmaceutical agent falls on the blood flow. Thus, presence of the radiopharmaceutical agent is expected in late images, since early presence suggests intravascular injection.²³

Lane et al.²⁹ performed lymphoscintigraphic studies every 10 minutes until completing 1 hour. Weissleder & Weissleder³⁰ considered normal that the radiopharmaceutical agent appears in lymph nodes within 10 minutes. Gloviczki et al.²¹ also established 10 minutes as the normal time for radiopharmaceutical transport, considering 1 hour as delayed transport and 2 hours as seriously compromised transport.

Control using the contralateral upper limb or control in the general population is suggested as a reference of normality for the lymphatic drainage pattern.¹⁹ The group evaluated using lymphoscintigraphy in the postoperative period without development of lymphedema has the functionality status similar to that of the control group.²⁹

Lymphoscintigraphy before and after axillary dissection has the potential of providing clinical information to predict the development of lymphatic changes that will culminate in the lymphedema.^19,26,27,31 Investigating the ipsilateral upper limb as to axillary dissection in the postoperative period without development of lymphedema is a proposal by Bourgeois et al.¹⁹ Little is known on preoperative lymphoscintigraphic study. It is believed that anatomical and functional changes present before the surgery are relevant in the development of lymphedema after axillary dissection. A single study reported 7.5% of lymphatic system abnormality in the preoperative period, and 85% of such abnormalities developed lymphedema at an approximate period of 34 months.¹⁹

Baulieu et al.³² evaluated 32 patients with edema secondary to tibia fracture surgery using lymphoscintigraphy, between 2 and 10 days after the surgery; the healthy limb was also assessed. Such patients were divided into two groups, and only the group with lymphatic impairment developed lymphedema over a 3-month period. Therefore, the authors could infer that preexistence of functional changes in the lymphatic system can justify early occurrence of lymphedema.

All these results are relative to patients that had all three Berg levels dissected and can be questioned, since most surgeons currently dissect levels I and II. However, the lymph nodes specifically related to upper limb drainage are located in the lateral part of the axillary dissection, below the axillary vein and above the second brachial intercostal nerve and are, therefore, present in Berg level I.³³

Another important finding shows that the axilla is completely dissected in only 1/3 of patients submitted to dissection of all three Berg levels, and this situation depends on the surgeon's experience. Thus, lymphatic drainage of the upper limb would be interrupted in 29.3% of patients, considering absence of radiopharmaceutical visualization in axillary lymph nodes using lymphoscintigraphy.¹⁹

In a multivariate analysis, Bourgeois et al.¹⁹ observed that three variables independently influence the fact that axillary lymph nodes are not seen: delay in postsurgery investigation/ patient's age (older than 60 years), and number of compromised lymph nodes (more than three).¹⁹

Evaluation of lymphatic system function of the lower limb ipsilateral to the affected breast, before and 60 days after surgery, provides knowledge of the previous functional status of the lymphatic system and its repercussion after axillary dissection, thus allowing for the description of potential predictive factors for the development of lymphedema. Previous evaluation of upper limbs ipsilateral and contralateral allows for the detection of clinical abnormalities and internal comparison of lymphatic distribution, providing a more reliable analysis of ipsilateral upper limb changes in the postoperative period.²³ Early evidence of such changes will foster the development of preventive measures, more rigorous follow-up of these patients, and possibly early diagnosis and treatment.

References

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Correspondence

Publication Dates

• Publication in this collection
  12 Dec 2008
• Date of issue
  Dec 2008

History

• Accepted
  14 Oct 2008
• Received
  17 July 2008