1 REVIEW ARTICLE Risk factors for breast cancer related lymphedema Avaliação dos fatores de risco no linfedema pós-tratamento de câncer de mama Laura Ferreira de Rezende 1, Alessandra Vilanova Reis Rocha 2, Caroline Silvestre Gomes 2 Abstract The main late complication after the surgery of breast cancer is the development of lymphedema, a chronic, progressive, usually incurable disease. The increase in the volume of the limb can disfigure the body image and develop the physical and psychological morbidity of the patient, promoting significant damage to the functions. This study was developed through a systematic review from the randomized crosschecking of the keywords lymphedema, lymphatic compensation, lymphatic system, axillary dissection, risk factors and breast cancer. Eighteen articles were selected, between 1979 and 2009, in which radiotherapy, axillary radiation, infection, axillary dissection followed by radiotherapy, obesity, number of removed and impaired lymph nodes and aggressiveness of surgery were found as main risk factors for the development of lymphedema. The way of compensation after the lymphatic axillary dissection, as the lympho-lymphatic anastomoses, may be hindered by scar formation, seroma after surgery, radiotherapy and inappropriate exercises for the shoulder rehabilitation in breast cancer. Keywords: Lymphedema; lymphatic system; lymph node excision; risk factors; breast neoplasms. Resumo A principal complicação tardia no pós-operatório de câncer de mama é o desenvolvimento do linfedema, uma doença crônica, progressiva, geralmente incurável. O aumento do volume do membro pode desfigurar a imagem corporal, assim como aumentar a morbidade física e psicológica da paciente, além de promover significativo prejuízo para as funções. O presente estudo foi desenvolvido por meio de uma revisão sistemática a partir do cruzamento aleatório das palavras-chave: linfedema, compensações linfáticas, sistema linfático, dissecção axilar, fatores de risco e câncer de mama. Foram selecionados 18 artigos entre os anos de 1979 e 2009, nos quais foram encontrados como principais fatores de risco para o desenvolvimento do linfedema a radioterapia, radioterapia axilar, infecção, dissecção axilar seguida de radioterapia, obesidade, número de linfonodos retirados e comprometidos e agressividade da cirurgia. As formas de compensação linfática após a dissecção axilar, como as anastomoses linfolinfáticas, podem ser prejudicadas pela formação cicatricial, seroma pós-operatório, radioterapia e exercícios inadequados para reabilitação de ombro no câncer de mama. Palavras-chave: Linfedema; sistema linfático; excisão de linfonodo; fatores de risco; neoplasias da mama. Introduction According to the International Society of Lymphology (ISL) 1, lymphedema is a clinical manifestation of insufficiency of the lymphatic system that results in a disorder of lymph transport. It may affect the face, chest, neck, limbs and pelvis and it is common in postoperative periods and radiotherapy for oncologic treatment. Besides that, there are: primary lymphedema due to lymphatic vascular malformations and secondary lymphedema, resulting from episodes of erysipelas or deep vein thrombosis, chronic vein insufficiency, trauma and ulcerations. Lymphedema is the postoperative complication of higher morbidity in breast cancer, as its adverse effects affect directly the patients quality of life. Although the incidence is decreasing due to early diagnosis and progress in therapeutic strategies - especially the sentinel lymph node biopsy - this entity remains a significant challenge for the patients and for the multidisciplinary team treating them 2. Despite those advances, the increase in breast cancer incidence and patients survival will inevitably increase the incidence of lymphedema 3. The estimates of incidence and prevalence of breast cancer-related lymphedema vary significantly in literature 1 PhD; Physical Therapist; Professor of the Physical Therapy graduation course at Centro Universitário das Faculdades Associadas de Ensino (FAE), São João da Boa Vista (SP), Brazil. 2 Physical Therapy student at Centro Universitário das Faculdades Associadas de Ensino (FAE), São João da Boa Vista (SP), Brazil. No conflicts of interest declared concerning the publication of this article. Received on: , Accepted on: J Vasc Bras. 2010;9(4):
2 234 J Vasc Bras 2010, Vol. 9, Nº 4 Lymphedema risk factors and breast cancer PO - Rezende LF et al. due to lack of standardization of criteria and methodological limitations of studies, along with variation of population sampling and duration of postoperative follow-up 4,5. Studies have reported several evaluation methods, including patients self-reported symptoms (for example, limb heaviness, pain, swelling and loss of function), objective measurements (using a variety of tools and protocols) and a combination of patients reports and objective measurements 6,7. The prevalence of lymphedema after breast cancer surgery varies significantly because there are no clear and uniform standards of evaluation. It is believed that this value varies from 24 to 49% after mastectomy, 4 to 28% after tumor resection with axillary dissection 8, and 34% after surgery and radiotherapy 9. The pathogenesis of post-mastectomy lymphedema has yet to be completely understood. A literature review shows there are as many theories as there are authors on the subject. As to the pathophysiology, lymphedema is characterized by a significant reduction in lymph transport, a mechanism necessary for the absorption of blood filtrate that accumulates in the insterstitial space 1. Lymphedema is a chronic, progressive and often incurable disease. The swelling of the limbs may disfigure the patient s body image, as well as increase the patient s physical and psychological morbidity, besides resulting in significant functional disability 9. Although there are satisfactory treatments available, the lack of knowledge about prevention and cure makes the professionals involved in a continuing search for better results 10. Lymphedema may be defined as an abnormal accumulation of protein in the insterstitial space, with edema and chronic inflammation of the extremity 11. It is the result of a functional overload of the lymphatic system, where lymph volume exceeds its transport capacity by lymphatic capillaries and collectors 12,13. The presence of proteins in the interstitial space triggers local fibrosis formation, impairing lymphatic circulation and contributing to the severity of the disease 14. Besides, axillary lymph node dissection will impair lymph transport capacity 15. Methods A systematic review was carried out, with the objective of evaluating the risk factors for the development of lymphedema in breast cancer postoperative period. We searched for papers published in the past 30 years that were indexed in Lilacs and Medline databases. The keywords used in the research were: lymphedema, lymphatic compensation, lymphatic system, axillary dissection, axillary lymphadenectomy, lymph nodes, risk factors, lymphatic drainage, breast cancer, and lymphoscintigraphy. We selected all papers whose objectives were related to: risk factors for lymphedema, incidence and onset of lymphedema, progression of lymphedema and lymphatic compensation after axillary dissection. Results Information presented in Table 1 is the result of the bibliographical survey on risk factors in postoperative breast cancer patients with and without lymphedema, aiming to determine the impact on lymphatic compensations in this period. Twenty-one papers were selected. The risk factors reported in the papers are presented in Table 1, while in Table 2 this relation is presented in numbers. Table 3 demonstrates the authors justification on how risk factors make lymphatic compensation more difficult and lead to lymphedema. Discussion About 140 million people worldwide have lymphedema: 20 million in the breast cancer postoperative period, which represents 98% of the upper limb lymphedemas 33. There are many factors associated with the risk of lymphedema development, and their interference in the lymphatic system compensation after axillary dissection may provide options of prevention and/or cure. This paper aimed to relate the risk factors considered to trigger the development of lymphedema with a possible explanation for the physiological organization of the lymphatic system facing each one of them. Knowledge of the factors and mechanisms involved in the development of lymphedema in the breast cancer postoperative period is essential for the prevention and cure of this disease. Surgical aggressiveness is a risk factor for lymphedema 10,17-19,24, which may explain the higher incidence in the mastectomy postoperative period in comparison with conservative surgery: 24 to 49% after mastectomy 4 to 28% after tumor resection with axillary dissection 9. One of the explanations would be that patients subjected to mastectomy usually have more advanced disease and need more aggressive axillary lymph node dissection due to tumor involvement. After the operation, weight gain may also be a risk factor 28. Axillary lymph node dissection is a well-known risk factor for lymphedema 10,16,18,21. Once axillary lymph nodes
3 Lymphedema risk factors and breast cancer PO - Rezende LF et al. J Vasc Bras 2010, Vol. 9, Nº Table 1 Risk factors related to lymphedema development in breast cancer postoperative period Publication Type of study Sample Risk factors Herd-Smith et al. 16 Cross-sectional patients in breast cancer PO Axillary lymph node dissection, RT Soran et al. 2 Case-control 104 in control group without lymphedema and 52 women with lymphedema Hayes et al. 17 Prospective 511 women with unilateral breast cancer, 75 years old. Aboul-Enein et al. 15 Case-control 40 women divided into 2 groups: with and without lymphedema. PO: postoperative; BMI: body mass index; RT: radiotherapy. Infection, BMI and level of activities performed with the hands Aging, surgery aggressiveness dissection of 20 or more lymph nodes, adjuvant therapy and RT Bergmann et al. 8 Cross-sectional 462 women with lymphedema in breast cancer PO Upper limb infection, axillary RT, obesity, reduced movements of the shoulder Pain et al. 18 Prospective 70 patients in breast cancer PO Axillary lymph node dissection Johansson et al. 19 Case-control 103 patients in breast cancer PO with lymphedema of the upper limb, but without recurrence. Lymphedema developed three months after surgery at minimum Ozaslan e Kuru 20 Prospective 240 patients in radical mastectomy PO with complete axillary dissection minimum 18 months of PO Erickson et al. 21 Literature review Axillary lymph node dissection and axillary RT - Purushotham et al. 22 Prospective 212 patients in breast cancer PO with axillary lymph node dissection - Extension and type of surgery, size of the tumor, number of lymph nodes removed and involved, postoperative seroma, infection, dehiscence, phlebitis, cellulites, erysipela in the upper limb and axillary RT Number of lymph nodes removed (univariate analysis), axillary RT and BMI Meeske et al. 23 Cross-sectional 494 patients in breast cancer PO Age at diagnosis, history of hypertension, obesity, 10 or more lymph nodes removed, sentinel lymph node Rett e Lopes 24 Literature review - Axillary dissection followed by RT; scar dehiscence, nervous lesions, venous alterations, infections, inflammation and upper limb seroma; positive lymph nodes, obesity, alteration in movement range, surgical technique Park et al. 25 Prospective 450 patients in breast cancer PO Advanced disease, mastectomy, axillary RT, BMI > 25. Nielsen et al. 26 Systematic review - - Ellis 27 Literature review Lymphatic system insufficiency by trauma, diseases or genetic factors Petrek et al. 28 Cohort 923 patients in breast cancer PO with axillary lymph node dissection - Infection and trauma in the upper limb, weight gain after surgery Rezende et al. 10 Literature review - Dissection and axillary RT, obesity, surgical extent and infection, age, number of lymph nodes involved Pain et al. 29 Prospective 18 patients in breast cancer PO - Bergmann et al. 30 Literature review - Axillary dissection, RT in drainage system and obesity. Freitas Jr et al. 31 Retrospective 109 patients in breast cancer PO Age and obesity Guedes Neto et al. 32 Retrospective 142 patients with post-mastectomy lymphedema Lymphangitis, functional limitations of the arm and basis disease recurrence. are removed, the main lymphatic collectors of the region have no path to continue the lymphatic drainage. The absence of lymph nodes causes an obstruction of the lymphatic system, leading to functional overload of the upper limb lymphatic system, where the lymph volume exceeds transport capacity by the lymphatic collectors and lymph absorption the capillaries 24. A risk factor of great importance in the literature is the number of removed and involved lymph nodes 10,19,20,24,25. Table 2 Risk factor with major influence on lymphedema development according to the selected papers Risk factor Papers (n) Obesity 10 Axillary lymph node dissection 8 Radiotherapy 7 Infection in the arm 6 Surgical aggressiveness 4
4 236 J Vasc Bras 2010, Vol. 9, Nº 4 Lymphedema risk factors and breast cancer PO - Rezende LF et al. Table 3 How the risk factors make the compensation of local lymphatic harder and lead to lymphedema Publication Herd-Smith et al. 16 Soran et al. 2 Aboul-Enein et al. 15 Bergmann et al. 8 Pain et al. 18 Johansson et al. 19 Ozaslan e Kuru 20 Purushotham et al. 22 Meeske et al. 23 Rett e Lopes 24 Nielsen et al. 26 Ellis 27 Rezende et al. 10 Pain et al. 29 PO: postoperative; RT: radiotherapy. Influence of risk factors for lymphedema on lymphatic compensations in axillary dissection PO RT would promote the formation of tissue fibrosis and consequent lymphatic vasoconstriction, deficit of lymph node filtration and alteration in the immunological response The formation of lymphatic anastomoses prevent lymphedema and, even without the manifestation of symptoms, most patients in breast cancer PO have lymphatic dysfunction The incidence of lymphedema is predetermined and a consequence of a failure in lymph-venous communication, which does not allow an adequate lymph fluid drainage after axillary dissection Due to lymphatic obstruction, compensation mechanisms develop to establish and maintain the lymphatic circulation in the affected upper limb without lymphedema. The longer the period of the lymphatic obstruction, the higher the risk of an unbalance in the system, thus causing lymphedema. This balance may also be affected by other factors such as: * exhaustion of compensation mechanism; *lymph vessels fibrosis from de fourth decade of life on; *local trauma; *surgical lesion in the collectors; *inflammation; *excessive muscle effort; *exposure to higher temperatures, atmospheric pressure and its changes Axillary dissection alters the flow into the axillary vein and increases the risk of lymphedema. Exercise may contribute to reduce the development of lymphedema because it activates lymphatic flow by contracting the skeletal muscle, improves the range of movements, and stimulates the immunological system. The obstruction of the lymphatic system is not the only mechanism of lymphedema physiopathology. The total blood flow and the size of the vascular bed seem to have increased the lymphedema. The tumoral involvement of lymph nodes requires greater axillary dissection, which would lead to a faster ability to develop collateral lymph vessels, promoting an adequate lymphatic drainage after the dissection and consequent risk reduction. Higher blood pressure enables lymphatic flow into the tissues. Younger patients are more prone to develop lymphedema as a result of the aggressiveness of the tumor and treatment Lymphedema results from a functional overload of the lymphatic system, since the lymph fluid exceeds the capacity of the collectors and lymphatic capillaries. Preventive guidelines are beneficial for preventing lymphedema. Lymphatic system deficit may result from trauma, diseases or genetic factors Lymphatic anastomoses are impaired by the healing process, postoperative seroma, RT and inadequate exercise for shoulder rehabilitation in breast cancer PO period. The restoration of the flow is benefited by the shoulder immobilization, manual lymphatic drainage and muscle contraction. The risk may be predetermined by a reduction of the lymphatic flow in the contralateral limb Bergmann et al. 30 RT in the lymphatic drainage system promotes a reduction of lymph regeneration, fibrosis and surgical wound healing A decrease in the blood and lymph flow is considered to be one of the conditions to lypogenesis and fat accumulation, besides increasing the risk of complications in PO The dissection of only the lymph system at the Nerg s level I may increase the risk. Freitas Jr et al. 31 Obesity would increase the risk due to a possible difficulty in lymphatic reflow in patients with more fat tissue. However, Purushotham et al. 22 suggest that lymph nodes involvement may prevent lymphedema because, as a consequence to axillary dissection, there is more time and ability for collateral lymph vessels to develop, which may promote an adequate drainage after this procedure and reduction of lymphedema risk. Another extensively discussed risk factor is axillary radiotherapy 8,10,16-21, a postoperative complementary treatment that causes destruction of lymph vessels resulting from the fibrosis, which may lead to significant loss of the lymph nodes filtration function and to an altered immunological response. Obesity 8,10,21,23,24 and body mass index 2,18,20,24 are widely discussed factors in literature. Meesk et al. 23 suggest the hypothesis that arterial hypertension is a risk factor, for the increase in blood flow would facilitate the lymphatic flow into tissues. Old age 10,17,24 is also mentioned as a risk factor because fibrosis of the lymphatic system occurs from the fourth decade of life on. Therefore, it is expected that the longer the period after lymphatic obstruction, the higher the risk of lymphatic failure, which leads to the development of lymphedema. Johansson et al. 19 suggest that the tumor size is a significant factor, since in young patients breast cancer
5 Lymphedema risk factors and breast cancer PO - Rezende LF et al. J Vasc Bras 2010, Vol. 9, Nº and its treatment tend to be more aggressive and there is a higher incidence of lymphedema. Sedentary lifestyle 17 and reduced shoulder range of motion 8,24 have been listed as probable risk factors, for exercises may contribute to the recovery from breast cancer treatment by re-opening lymph vessels, activating the lymphatic flow by skeletal muscle contraction, improving range of motion, and stimulating the immune system. Infection is also a risk factor 2,8,10,18,19,21,24,27,28. Episodes of phlebitis 19, cellulitis and erysipelas of the upper limbs 19,21 are frequently discussed as resulting in lymphatic obstruction. Postoperative seroma and scar maturation may be risk factors 18,24 because lymphatic anastomoses are impaired by scar tissue formation related to the seroma itself 27. Conclusions Currently, studies on lymphedema found in the literature show a satisfactory knowledge about treatment and follow-up of patients with this disease. However, many questions remain to be discussed on the etiopathogenesis of this disease. Health care professionals should use the knowledge of well-defined risk factors as tools to inform and instruct patients. Orienting patients about risk factors that have already been established is essential. Many factors have been discussed in literature, but there is still the need for further studies to explain the role of each of those factors on the formation of lymphatic anastomoses, on lymphatic compensations and on the subsequent incidence of lymphedema. References 1. International Society of Limphology. The diagnosis and treatment of peripheral lymphedema. Consensus document of the International Society of Lymphology. Lymphology. 2003;36: Soran A, D angelo G, Begovic M, et al. Breast cancer-related lymphedema what are the significant predictors and how they affect the severity of lymphdema? Breast J. 2006;12: Szuba A, Shin WS, Strauss W, Rockson S. The third circulation: radionuclide lymphoscintigraphy in the evaluation of lymphedema. J Nucl Med. 2003;44: Petrek JA, Heelan MC. Incidence of breast carcinoma-related lymphedema. Cancer. 1998;83(12 Suppl American): McCredie MR, Dite GS, Porter L, et al. Prevalence of self-reported arm morbidity following treatment for breast cancer in the Australian Breast Cancer Family Study. Breast. 2001;10: Duff M, Hill AD, McGreal G, Walsh S, McDermott EW, O Higgins NJ. Prospective evaluation of the morbidity of axillary clearance for breast cancer. Br J Surg. 2001;88: Kwan W, Jackson J, Weir LM, Dingee C, McGregor G, Olivotto IA. Chronic arm morbidity after curative breast cancer treatment: prevalence and impact on quality of life. J Clin Oncol. 2002;20: Bergmann A, Mattos IE, Koifman RJ. Diagnótico do linfedema: análise dos métodos empregados na avaliação do membro superior após linfadenectomia axilar para tratamento do câncer de mama. Rev Bras Cancerol. 2004;50: Warren AG, Brorson H, Borud LJ, Slavin SA. Lymphedema: a comprehensive review. Ann Plast Surg. 2007;59: Rezende LF, Pedras FV, Ramos CD, Gurgel MSC. Avaliação das compensações linfáticas no pós-operatório de câncer de mama com dissecção axilar através da linfocintilografia. J Vasc Bras. 2008;7: Brennan MJ, DePompolo RW, Garden FH. Focused review: postmastectomy lymphedema. Arch Phys Med Rehabil. 1996,77(3 Suppl):S Bernas MJ, Witte CL, Witte MH; International Society of Lymphology Executive Committee. The diagnosis and treatment of peripheral lymphedema: draft revision of the 1995 Consensus Document of the International Society of Lymphology Executive Committee for discussion at the September 3-7, 2001, XVIII International Congress of Lymphology in Genoa, Italy. Lymphology. 2001;34: Camargo M, Marx A. Reabilitação física no câncer de mama. São Paulo: Roca; Burt J, White G. Lymphedema. In: Burt J, White G. Lymphedema: a breast cancer patient s guide to prevention and healing. New York: Hunter House Publishers; 1999; p Aboul-Enein A, Eshmawy I, Arafa S, Abboud A. The role of lymphovenous communication in the development of postmastectomy lymphedema. Surgery. 1984;95: Herd-Smith A, Russo A, Muraca MG, Del Turco MR, Cardona G. Prognostic factors for lymphedema after primary treatment of breast carcinoma. Cancer. 2001;92: Hayes SC, Janda M, Cornish B, Battistutta D, Newman B. Lymphedema after breast cancer: incidence, risk factors, and effect on upper body function. J Clin Oncol. 2008,26: Pain SJ, Vowler S, Purushotham AD. Axillary vein abnormalities contribute to development of lymphoedema after surgery for breast cancer. Br J Surgery. 2005,92: Johansson K, Ohlsson K, Ingvar C, Albertsson M, Ekdahl C. Factors associated with the development of arm lymphedema following breast cancer treatment: a match pair case-control study. Lymphology. 2002;35: Ozaslan C, Kuru B. Lymphedema after treatment of breast cancer. Am J Surg. 2004;187: Erickson VS, Pearson ML, Ganz PA, Adams J, Kahn KL. Arm edema in breast cancer patients. J Natl Cancer Inst. 2001;93: Purushotham AD, Bennett Britton TM, Klevesath MB, Chou P, Agbaje OF, Duffy SW. Lymph node status and breast cancer-related lymphedema. Ann Surg. 2007;246: Meeske KA, Sullivan-Halley J, Smith AW, McTiernan A, Baumgartner KB, Harlan LC, et al. Risk factors for arm lymphedema following breast cancer diagnosis in Black women and White women. Breast Cancer Res Treat. 2009;113:
6 238 J Vasc Bras 2010, Vol. 9, Nº 4 Lymphedema risk factors and breast cancer PO - Rezende LF et al. 24. Rett MT, Lopes MCA. Fatores de risco relacionados ao linfedema. Rev Bras Mastologia. 2002;12: Park JH, Lee WH, Chung HS. Incidence and risk factors of breast cancer lymphoedema. J Clin Nurs. 2008;17: Nielsen I, Gordon S, Selby A. Breast cancer-related lymphoedema risk reduction advice: a challenge for health professionals. Cancer Treat Rev. 2008;34: Ellis S. Structure and function of the lymphatic system: an overview. The Lymphoedema Supplement. Br J Community Nurs. 2006;11(4 Suppl):S4-S Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer. 2001,92: Pain SJ, Purushotham AD, Barber RW, Ballinger JR, Solanki CK, Mortimer PS, et al. Variation in lymphatic function may predispose to development of breast cancer-related lymphoedema. Eur J Surg Oncol. 2004,30: Bergmann A, Mattos IE, Kofman RJ. Fatores de risco para linfedema após câncer de mama: uma revisão da literatura. Fisioter pesqui. 2008,15: Freitas Jr R, Ribeiro LFJ, Taia L, Kajita D, Fernandes MV, Queiroz GS. Linfedema em pacientes submetidos à mastectomia radical modificada. Rev Bras Ginecol Obstet. 2001;23: Guedes Neto HJ, Kupsinskas Junior AJ, Stuart S, Barbosa EM, Bacarat FF. Considerações sobre linfedema pós-mastectomia. Cir Vasc Angiol. 1995;11: Campisi C, Michelini S, Boccardo F. Guidelines of the Societá Italiana di Linfangiologia. Lymphology. 2004;37: Correspondence: Laura Ferreira de Rezende Franco Largo Engenheiro Paulo de Almeida Sandeville, 15 Santo André CEP São João da Boa Vista (SP), Brazil Authors contribution: Study conception and design: LFR Data analysis and interpretation: LFR, AVRR and CSG Data collection: LFR, AVRR and CSG Writing: LFR, AVRR and CSG Critical analysis: LFR Final text approval *: LFR, AVRR and CSG * All authors have read and approved the final version of the paper submitted to the J Vasc Bras.