Issues
Upper extremity lymphedema after radiation therapy, chemotherapy and surgical treatment of breast cancer. Part 1. Epidemiology, factors affecting the frequency of occurrence, classification, staging, diagnosis, differential diagnosis. Review
«Radiation and Risk», 2025, vol. 34, No. 3, pp.146-165
DOI: 10.21870/0131-3878-2025-34-3-146-165
Authors
Kuleshov I.N. – Surgeon. Contacts: 4 Korolyov str., Obninsk, Kaluga region, Russia, 249035. Tel.: +7(910)597-03-93; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .Kursova L.V. – Lead. Researcher, C. Sc., Med.
Korotkov V.A. – Head of Dep., C. Sc., Med.
Shitareva V.N. – Jun. Researcher
Pasov V.V. – Lead. Researcher, MD
Iofik V.V. – Researcher, C. Sc., Med.
Kasymov M.R. – Oncologist
Ivanov S.A. – Director, Corr. Member of RAS, MD, Prof. of RUDN University Dep. A. Tsyb MRRC.
Ulyanov A.A. – Surgeon. Clinic “Astro”.
Kaprin A.D. – General Director, Director of P. Hertsen MORI, Head of RUDN University Dep., Academician of RAS, MD, Prof. NMRRC.
1 A. Tsyb MRRC, Obninsk
2 Clinic «Astro», Obninsk
3 Peoples' Friendship University of Russia named after Patrice Lumumba, Moscow
4 NMRRC, Obninsk
5 P. Hertsen MORI, Moscow
Abstract
Breast cancer is the leading malignant neoplasm in women in terms of frequency of occurrence. In its treatment, techniques including surgical interventions, radiation and chemotherapy are used. Despite the improvement of radiotherapy techniques and approaches to surgical interventions, various complications of antitumor treatment are still encountered. The most frequent among them is the development of upper limb lymphedema, which significantly reduces the quality of life of patients. The incidence of this disease varies considerably; according to various researchers, it can occur in 3-40% of patients after breast cancer treatment. A large number of factors have been identified that can influence this rate. Among them are the volume of surgery, radiation therapy regimens, chemo-therapy regimens, as well as high body mass index of the patient, comorbidity, smoking and many others. Now, there is no unified approach to the criteria for diagnosis and staging of this disease. Despite considerable experience in diagnosing lymphedema of the upper extremities, the diagnosis may be complicated by the presence of pathology with similar symptomatology. Most often, these are various disorders of venous circulation, causing edema and increase in volume of the limb. This review considers the epidemiology of upper limb lymphedema after breast cancer treatment, factors influencing the incidence of this disease, approaches to its classification and staging, as well as the issues of diagnosis and differential diagnosis.
Key words
radiation therapy, breast cancer, chemotherapy, surgical treatment, upper extremity lymphedema, combined treatment of breast cancer, epidemiology.
References
1. Bowman C., Rockson S.G. The role of inflammation in lymphedema: a narrative review of pathogenesis and opportunities for therapeutic intervention. Int. J. Mol. Sci., 2024, vol. 25, no. 7, pp. 3907. DOI: 10.3390/ijms25073907.
2. Swaroop M.N., Ferguson C.M., Horick N.K., Skolny M.N., Miller C.L., Jammallo L.S., Brunelle C.L., O'Toole J.A., Isakoff S.J., Specht M.C., Taghian A.G. Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort. Breast Cancer Res. Treat., 2015, vol. 151, no. 2, pp. 393-403.
3. Kuruvilla A.S., Krajewski A., Li X., Yang J., Mulay S.R., Agha S.M., Kohli H.K., Bellis R.M., Tannous H.J., Shroyer A.L.W. Risk factors associated with postmastectomy breast cancer lymphedema: a multicenter ret-rospective analysis. Ann. Plast. Surg., 2022, vol. 88, no. 3 (Suppl. 3), pp. S239-S245.
4. Byun H.K., Chang J.S., Im S.H., Kirova Y.M., Arsene-Henry A., Choi S.H., Cho Y.U., Park H.S., Kim J.Y., Suh C.O., Keum K.C., Sohn J.H., Kim G.M., Lee I.J., Kim J.W., Kim Y.B. Risk of lymphedema following contemporary treatment for breast cancer: an analysis of 7617 consecutive patients from a multidisciplinary perspective. Ann. Surg., 2021, vol. 274, no. 1, pp. 170-178.
5. McDuff S.G.R., Mina A.I., Brunelle C.L., Salama L., Warren L.E.G., Abouegylah M., Swaroop M., Skolny M.N., Asdourian M., Gillespie T., Daniell K., Sayegh H.E., Naoum G.E., Zheng H., Taghian A.G. Timing of lymphedema after treatment for breast cancer: when are patients most at risk? Int. J. Radiat. Oncol. Biol. Phys., 2019, vol. 103, no. 1, pp. 62-70.
6. Hara Y., Otsubo R., Shinohara S., Morita M., Kuba S., Matsumoto M., Yamanouchi K., Yano H., Eguchi S., Nagayasu T. Lymphedema after axillary lymph node dissection in breast cancer: prevalence and risk factors-a single-center retrospective study. Lymphat. Res. Biol., 2022, vol. 20, no. 6, pp. 600-606.
7. DiSipio T., Rye S., Newman B., Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol., 2013, vol. 14, no. 6, pp. 500-115.
8. Bell R.J., Robinson P.J., Barallon R., Fradkin P., Schwarz M., Davis S.R. Lymphedema: experience of a cohort of women with breast cancer followed for 4 years after diagnosis in Victoria, Australia. Support. Care Cancer, 2013, vol. 21, no. 7, pp. 2017-2024.
9. Doś J., Gutowski P., Górska-Doś M. Incidence and risk factors of lymphedema in women after surgery for breast cancer. Ann. Acad. Med. Stetin., 2009, vol. 55, no. 2, pp. 30-34.
10. Ribeiro Pereira A.C.P., Koifman R.J., Bergmann A. Incidence and risk factors of lymphedema after breast cancer treatment: 10 years of follow-up. Breast, 2017, vol. 36, pp. 67-73.
11. Liu Y.F., Liu J.E., Mak Y.W., Zhu Y., Qiu H., Liu L.H., Yang S.S., Chen S.H. Prevalence and predictors of breast cancer-related arm lymphedema over a 10-year period in postoperative breast cancer patients: a cross-sectional study. Eur. J. Oncol Nurs., 2021, vol. 51, pp. 101909. DOI: 10.1016/j.ejon.2021.101909.
12. Ahmed R.L., Prizment A., Lazovich D., Schmitz K.H., Folsom A.R. Lymphedema and quality of life in breast cancer survivors: the Iowa Women's Health Study. J. Clin Oncol., 2008, vol. 26, no. 35, pp. 5689-5696.
13. Rupp J., Hadamitzky C., Henkenberens C., Christiansen H., Steinmann D., Bruns F. Frequency and risk factors for arm lymphedema after multimodal breast-conserving treatment of nodal positive breast cancer – a long-term observation. Radiat Oncol., 2019, vol. 14, no. 1, pp. 39. DOI: 10.1186/s13014-019-1243-y.
14. Kim H.K., Ju Y.W., Lee J.W., Kim K.E., Jung J., Kim Y., Lee H.B., Moon H.G., Noh D.Y., Seo K.S., Han W. Association between number of retrieved sentinel lymph nodes and breast cancer-related lymphedema. J. Breast Cancer, 2021, vol. 24, no. 1, pp. 63-74.
15. Ogiya A., Kimura K., Ueno T., Iwase T., Ohno S. Time trend of breast cancer-related lymphedema according to body mass index. Eur J. Surg Oncol., 2024, vol. 50, no. 6, pp. 108350. DOI: 10.1016/j.ejso.2024.108350.
16. Peng X., Chen R., Rao Z., Yang Y., Yan Y., Xia Y., Wang T., Wang J., Lu F., Pan H., Liu Y., Cheng J., He Q. High recurrence of lymphedema and influencing factors in discharged breast cancer patients during the COVID-19 pandemic: a multicenter, cross-sectional survey. Cancer Med., 2022, vol. 11, no. 19, pp. 3572-3580.
17. McNeely M.L., Courneya K.S., Al Onazi M.M., Wharton S., Wang Q., Dickau L., Vallance J.K., Culos-Reed S.N., Matthews C.E., Yang L., Friedenreich C.M. Upper limb morbidity in newly diagnosed individuals after unilateral surgery for breast cancer: baseline results from the AMBER cohort study. Ann. Surg. Oncol., 2023, vol. 30, no. 13, pp. 8389-8397.
18. Johnson A.R., Kimball S., Epstein S., Recht A., Lin S.J., Lee B.T., James T.A., Singhal D. Lymphedema incidence after axillary lymph node dissection: quantifying the impact of radiation and the lymphatic microsur-gical preventive healing approach. Ann. Plast. Surg., 2019, vol. 82, no. 4S (Suppl 3), pp. S234-S241.
19. Jinbo K., Fujita T., Kasahara R., Jinbo R., Kisara S., Onobe J., Kimijima I., Yasuda M., Yamamoto Y. The effect of combined risk factors on breast cancer-related lymphedema: a study using decision trees. Breast Cancer, 2023, vol. 30, no. 4, pp. 685-688.
20. Huang Y.Y., Toh P.Y., Hunt C., Lin J.T.W., Kamyab R., Ponniah A.K. Breast cancer treatment-related arm lymphoedema and morbidity: a 6-year experience in an Australian tertiary breast centre. Asia Pac. J. Clin. Oncol., 2022, vol. 18, no. 1, pp. 109-117.
21. Paskett E.D., Naughton M.J., McCoy T.P., Case L.D., Abbott J.M. The epidemiology of arm and hand swelling in premenopausal breast cancer survivors. Cancer Epidemiol. Biomarkers Prev., 2007, vol. 16, no. 4, pp. 775-782.
22. Martínez-Jaimez P., Armora Verdú M., Forero C.G., Álvarez Salazar S., Fuster Linares P., Monforte-Royo C., Masia J. Breast cancer-related lymphoedema: risk factors and prediction model. J. Adv. Nurs., 2022, vol. 78, no. 3, pp. 765-775.
23. Card A., Crosby M.A., Liu J., Lindstrom W.A., Lucci A., Chang D.W. Reduced incidence of breast cancer-related lymphedema following mastectomy and breast reconstruction versus mastectomy alone. Plast. Reconstr. Surg., 2012, vol. 130, no. 6, pp. 1169-1178.
24. Shaitelman S.F., Chiang Y.J., Griffin K.D., DeSnyder S.M., Smith B.D., Schaverien M.V., Woodward W.A., Cormier J.N. Radiation therapy targets and the risk of breast cancer-related lymphedema: a systematic review and network meta-analysis. Breast Cancer Res. Treat., 2017, vol. 162, no. 2, pp. 201-215.
25. Warren L.E., Miller C.L., Horick N., Skolny M.N., Jammallo L.S., Sadek B.T., Shenouda M.N., O'Toole J.A., MacDonald S.M., Specht M.C., Taghian A.G. The impact of radiation therapy on the risk of lymphedema after treatment for breast cancer: a prospective cohort study. Int. J. Radiat. Oncol. Biol. Phys., 2014, vol. 88, no. 3, pp. 565-571.
26. Lin Y., Xu Y., Wang C., Song Y., Huang X., Zhang X., Cao X., Sun Q. Loco-regional therapy and the risk of breast cancer-related lymphedema: a systematic review and meta-analysis. Breast Cancer, 2021, vol. 28, no. 6, pp. 1261-1272.
27. Stolarz A.J., Lakkad M., Klimberg V.S., Painter J.T. Calcium channel blockers and risk of lymphedema among breast cancer patients: nested case-control study. Cancer Epidemiol. Biomarkers Prev., 2019, vol. 28, no. 11, pp. 1809-1815.
28. Tyulyandin S.A., Garin A.M., Gorbunova V.A. Taxanes – new antitumor drugs of plant origin with a unique mechanism of action. Vestnik ONTs RAMN – Journal of Cancer Research Center RAMS, 1993, vol. 4, no. S, pp. 96-101. (In Russian).
29. Lai J.I., Chao T.C., Liu C.Y., Huang C.C., Tseng L.M. A systemic review of taxanes and their side effects in metastatic breast cancer. Front. Oncol., 2022, vol. 12, pp. 940239. DOI: 10.3389/fonc.2022.940239.
30. Tokumoto H., Akita S., Nakamura R., Yamamoto N., Kubota Y., Mitsukawa N. Investigation of the associ-ation between breast cancer-related lymphedema and the side effects of taxane-based chemotherapy using indocyanine green lymphography. Lymphat. Res. Biol., 2022, vol. 20, no. 6, pp. 612-617.
31. Paramanandam V.S., Dylke E., Clark G.M., Daptardar A.A., Kulkarni A.M., Nair N.S., Badwe R.A., Kilbreath S.L. Prophylactic use of compression sleeves reduces the incidence of arm swelling in women at high risk of breast cancer-related lymphedema: a randomized controlled trial. J. Clin. Oncol., 2022, vol. 40, no. 18, pp. 2004-2012.
32. Morfoisse F., Zamora A., Marchaud E., Nougue M., Diallo L.H., David F., Roussel E., Lacazette E., Prats A.C., Tatin F., Garmy-Susini B. Sex hormones in lymphedema. Cancers (Basel), 2021. vol. 13, no. 3, pp. 530. DOI: 10.3390/cancers13030530.
33. De Giorgi A., Di Simone E., Cappadona R., Boari B., Savriè C., López-Soto P.J., Rodríguez-Borrego M.A., Gallerani M., Manfredini R., Fabbian F. Validation and comparison of a modified Elixhauser index for pre-dicting in-hospital mortality in Italian internal medicine wards. Risk Manag. Healthc. Policy, 2020. vol. 13, pp. 443-451.
34. Wang L., Chen H., Li Y., Wang H., Liu N., Yu M., Shang S. Body mass index increases the risk of breast cancer-related lymphedema at 6-18 months after surgery: a retrospective study. Support. Care Cancer, 2023, vol. 31, no. 5, pp. 278. DOI: 10.1007/s00520-023-07721-7.
35. Inghammar M., Rasmussen M., Linder A. Recurrent erysipelas – risk factors and clinical presentation. BMC Infect. Dis., 2014, vol. 4. p. 270. DOI: 10.1186/1471-2334-14-270.
36. Brishkoska-Boshkovski V., Kondova-Topuzovska I., Damevska K., Petrov A. Comorbidities as risk fac-tors for acute and recurrent erysipelas. Open Access. Maced. J. Med. Sci., 2019, vol. 7, no. 6, pp. 937-942.
37. Feyskhanov A.K., Fatykhova E.Z., Feyskhanova L.I., Maksimov A.V. Swelling and lymphedema. Prakticheskaya meditsina – Practical Medicine, 2016, vol. 1, no. 4, pp. 161-164. (In Russian).
38. Baird J.B., Charles J.L., Streit T.G., Roberts J.M., Addiss D.G., Lammie P.J. Reactivity to bacterial, fungal, and parasite antigens in patients with lymphedema and elephantiasis. Am. J. Trop. Med. Hyg., 2002, vol. 66, no. 2, pp. 163-169.
39. Executive Committee of the International Society of Lymphology. The diagnosis and treatment of periph-eral lymphedema: 2020 Consensus Document of the International Society of Lymphology. Lymphology, 2020, vol. 53, no. 1, pp. 3-19.
40. Norman S.A., Miller L.T., Erikson H.B., Norman M.F., McCorkle R. Development and validation of a tele-phone questionnaire to characterize lymphedema in women treated for breast cancer. Phys. Ther., 2001, vol. 81, no. 6, pp. 1192-1205.
41. Karlsson K., Nilsson-Wikmar L., Brogårdh C., Johansson K. Palpation of increased skin and subcutane-ous thickness, tissue dielectric constant, and water displacement method for diagnosis of early mild arm lymphedema. Lymphat. Res. Biol., 2020, vol. 18, no. 3, pp. 219-225.
42. Kim G., Donohoe K., Smith M.P., Hamaguchi R., Johnson A.R., Singhal D., Tsai L.L. Use of non-contrast MR in diagnosing secondary lymphedema of the upper extremities. Clin. Imaging, 2021, vol. 80, pp. 400-405.
43. Dustmann H.O. Diagnosis, differential diagnosis and therapy of lymphedema. Z. Orthop. Ihre. Grenzgeb., 1982, vol. 120, no. 1, pp. 76-82.
44. Kageyama T., Shiko Y., Kawasaki Y., Miyazaki T., Sakai H., Tsukuura R., Yamamoto T. Three-dimen-sional non-contrast magnetic resonance lymphography severity stage for upper extremity lymphedema. Magn. Reson. Imaging, 2024, vol. 107, pp. 24-32.
45. Soran A., Bengur F.B., Rodriguez W., Chroneos M.Z., Sezgin E. Early detection of breast cancer-related lymphedema: accuracy of indocyanine green lymphography compared with bioimpedance spectroscopy and subclinical lymphedema symptoms. Lymphat. Res. Biol., 2023, vol. 21, no. 4, pp. 359-365.
46. Tokumoto H., Akita S., Kubota Y., Mitsukawa N. Relationship between the circumference difference and findings of indocyanine green lymphography in breast cancer-related lymphedema. Ann. Plast. Surg., 2022, vol. 88, no. 1, pp. 114-117.
47. Park J.W., Hwang J.W., Woo K.J. Lymphatic flow velocity is a predictor of functional lymphatic vessels for lymphaticovenous anastomosis. J. Plast. Reconstr. Aesthet. Surg., 2023, vol. 82, pp. 219-228.
48. Seki Y., Kajikawa A., Yamamoto T., Takeuchi T., Terashima T., Kurogi N. Real-time indocyanine green videolymphography navigation for lymphaticovenular anastomosis. Plast. Reconstr. Surg. Glob. Open, 2019, vol. 7, no. 5, pp. e2253. DOI: 10.1097/GOX.0000000000002253.
49. Ter S.E., Alavi A., Kim C.K., Merli G. Lymphoscintigraphy. A reliable test for the diagnosis of lymphedema. Clin. Nucl. Med., 1993, vol. 18, no. 8, pp. 646-654.
50. Infante J.R., García L., Laguna P., Durán C., Rayo J.I., Serrano J., Domínguez M.L., Sánchez R. Lym-phoscintigraphy for differential diagnosis of peripheral edema: diagnostic yield of different scintigraphic pat-terns. Rev. Esp. Med. Nucl. Imagen. Mol., 2012, vol. 31, no. 5, pp. 237-242.
51. Kim K., Kim I.J., Pak K., Kim S.J., Choi S.J., Park H., Kang T., Kong I.J., Shin Y.B., Kim H., Yoon J.A. The feasibility of quantitative parameters of lymphoscintigraphy without significant dermal backflow for the evaluation of lymphedema in post-operative patients with breast cancer. Eur. J. Nucl. Med. Mol. Imaging, 2020, vol. 47, no. 5, pp. 1094-1102.
52. Christian M.M., Murphy C.M., Wagner R.F.Jr. Metastatic basal cell carcinoma presenting as unilateral lymphedema. Dermatol. Surg., 1998, vol. 24, no. 10, pp. 1151-1153.
53. Vignes S. Secondary limb lymphedema. Presse Med., 2010, vol. 39, no. 12, pp. 1287-1291.
54. Nacchiero E., Di Candia M., Nacchiero M., Pascone M. An unusual tumor in a rare localization: intravascular leiomyosarcoma of the cephalic vein. Case report. Ann. Ital. Chir., 2013, vol. 84, no. 3, pp. 311-313.
55. Maldjian C., Khanna V., Tandon B., Then M., Yassin M., Adam R., Klein M.J. Lymphatic filariasis dissem-inating to the upper extremity. Case Rep. Radiol., 2014, vol. 2014, p. 985680. DOI: 10.1155/2014/985680.
56. Aytekin E., Dogan Y.P., Okur S.C., Burnaz O., Caglar N.S. Differential diagnosis of a rare case of upper limb pain: Paget-Schroetter syndrome in a doner kebab chef. J. Phys. Ther. Sci., 2015, vol. 27, no. 10, pp. 3333-3335.
57. Jourdain V., Goldenberg W.D., Matteucci M., Auten J. Paget-Schroetter syndrome: diagnostic limitations of imaging upper extremity deep vein thrombosis. Am. J. Emerg Med., 2016, vol. 34, no. 3, pp. 683. DOI: 10.1016/j.ajem.2015.07.018.
58. Hariz A., Guermazi M., Hamdi M.S., Boukhris I. Deep vein thrombosis of the left arm revealing an asymptomatic pulmonary tuberculosis. BMJ Case Rep., 2019, vol. 12, no. 6, pp. e229484. DOI: 10.1136/bcr-2019-229484.
59. Elias A., Debourdeau P., Espitia O., Sevestre M.A., Girard P., Mahé I., Sanchez O. Central venous catheter associated upper extremity deep vein thrombosis in cancer patients: diagnosis and therapeutic management. Arch. Cardiovasc. Dis. 2024, vol. 117, no. 1, pp. 72-83.
60. Sahota R.J., Lotfollahzadeh S., Soos M.P. Subclavian vein thrombosis. StatPearls [Internet]. Treasure Island (FL), StatPearls Publishing, 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK559269/ (Accessed 28.08.2025).
61. Trezza C., Califano C., Iovino V., D'Ambrosio C., Grimaldi G., Pittiruti M. Incidence of fibroblastic sleeve and of catheter-related venous thrombosis in peripherally inserted central catheters: a prospective study on oncological and hematological patients. J. Vasc. Access., 2021, vol. 22, no. 3, pp. 444-449.
62. Chantalat L., Simon M., Fourgeaud C., Vignes S. Puffy hand syndrome: a little-known diagnosis. Rev. Med. Interne, 2020, vol. 41, no. 10, pp. 700-703.
63. Mihara M., Hara H., Murai N., Todokoro T., Iida T., Narushima M., Koshima I. Severe lymphedema caused by repeated self-injury. Lymphology, 2011, vol. 44, no. 4, pp. 183-186.
