Lymphedema is a disease in which fluids and proteins accumulate in local tissues due to damage to the lymphatic system. It may be asymptomatic or accompanied by symptoms such as heaviness and pain [1, 2]. Lymphedema in the lower extremities has various causes. The most common is damage to the lymphatic system after gynecological cancer surgery [3]. The incidence of gynecological cancers is increasing in Korea and survival rates are also increasing. Therefore, management of cancer survivors is emerging as an important problem [4, 5]. Lymphedema of the lower extremities is a representative complication after gynecologic cancer treatment. The incidence is reported to be from 10% to 70%, with unilateral lymphedema accounting for 80% and bilateral lymphedema accounting for 20% [3, 6-8]. Patients with lymphedema can undergo conservative or surgical treatments, but lymphedema is not yet curable. Lymphedema of the lower extremities leads to a decrease in patient quality of life [9]. Patients with bilateral lymphedema of the lower extremities complain of more discomfort than patients with unilateral lymphedema and can have gait disturbances [10]. Lymphedema of the upper limbs that occurs after breast cancer surgery is unilateral, but lymphedema after gynecological cancer surgery may be unilateral or bilateral. Therefore, predicting if lymphedema will occur unilaterally or bilaterally in patients who had gynecological cancer surgery is necessary but the factors causing bilateral lymphedema are unknown. In this study, we compared groups of patients with bilateral and unilateral lower limb lymphedema to determine which factors influence the development of bilateral lymphedema.

Group A had 71 patients with a mean age of 52.24 ± 11.47 years, group B had 27 patients with a mean age of 53.07 ± 12.39, and group C had 12 patients, with a mean age of 54.08 ± 13.53. The duration of lymphedema development was 35.43 ± 29.19 days on average, and there was no statistically significant difference when comparing the mean through Independent Sample t Test. Group A had 49 patients with cervical cancer and 11 each with ovarian and endometrial cancer. Group B had 14 with cervical, 12 with ovarian, and 2 with endometrial, and C had 10, 1 and 1, respectively. Mean BMI was 24.11 ± 3.62 with 70 patients with a BMI of 23 or more. In addition, 49 patients received radiation therapy, and 82 patients received chemotherapy. Lymphangitis developed in 59 patients and genital swelling in 48 (Table 1). Age, BMI, radiation therapy, chemotherapy, and lymphangitis were not significantly different between groups A and B. However, the types of cancer, cancer stage, and genital swelling were significantly different between the two groups (Table 2). Exact logistic regression analysis showed that cancer stage and genital swelling were associated with bilateral lymphedema (Table 3). No significant difference was seen in age, type of cancer, cancer stage, BMI, chemotherapy or genital swelling between groups A and C. Significant differences were observed for radiation therapy and lymphangitis (Table 4). Exact logistic regression analysis revealed that radiation therapy and lymphangitis were factors associated with unilateral to bilateral progression (Table 5). A total of 82 patients were identified by extent of lymph node dissection with 52 in group A, 23 in B, and 7 in C groups. In comparisons between groups A and B, the extent of lymph node dissection was significantly different (Table 2). However, comparisons between groups A and C showed no significant differences.

In comparisons of groups A and B, cancer type, cancer stage, and genital swelling were significantly different. Patients with bilateral lymphedema had a higher cancer stage than those with unilateral lymphedema. Ovarian cancer was seen in a higher proportion of patients in group B than group A. However, in exact logistic regression, the cancer type was not significant. Ovarian cancer patients with higher stage cancer undergo cytoreduction surgery to reduce cancer volume [13]. Cytoreductive surgery is often performed with extensive lymph node dissection. Although exact logistic regression analysis was not performed due to the small number of patients with confirmed records for lymph node dissection, a significant difference was seen for lymph node dissection in groups A and B. This result meant that extensive lymph node dissection increased the likelihood of bilateral lymphedema in the lower extremities. The wider the lymph node dissection in high stage cancer, the greater the likelihood of bilateral lymphedema. Therefore, it is believed that bilateral lymphedema in high stage ovarian cancer is not a characteristic of ovarian cancer, but an influence of extensive lymph node dissection. Genital swelling was significantly higher in group B than group A, indicating that it was associated with bilateral lower limb lymphedema. Genital lymphedema is an abnormality in the proximal lymphatic system, which is more likely to drain on both sides because the lymph nodes are closer to each other than in distal regions [14, 15]. Patients with bilateral lymphedema are more likely to have damage to the proximal region because both lymphatic systems are injured. For this reason, patients with bilateral lymphedema are more likely to have genital swelling than patients with unilateral lymphedema.

We found a significant difference in radiation treatment and infection history between groups A and C. Patients who received radiation therapy were more likely to progress from unilateral to bilateral lymphedema, so continuous outpatient follow-up should examine for circumferential changes in the leg where no edema has occurred. If swelling occurs in the lower extremity that was normal in unilateral lymphedema patients, lymphoscintigraphy should be redone to check for changes in the patient's lymphatic system. Infection causes inflammation of the tissues, which can damage the lymphatic system. In breast cancer-related lymphedema, infection is a major risk factor for lymphedema aggravation [16]. In our study, infection was also a factor in the progression of unilateral into bilateral lymphedema. Radiation therapy was significantly different in comparisons of groups A and C, but not groups A and B. McDuff’s study, which focused on the timing of lymphedema following breast cancer treatment, showed that regional lymph node radiation is associated with late onset lymphedema [17]. Both that and our study indicated that radiation therapy is the cause of delayed lymphedema. Therefore, further research should be conducted to identify why radiation therapy causes delayed lymphedema. Infection is one of the common complications in patients with lymphedema and is known to be mainly caused by wounds [18]. If patients pay attention to skin care, infection is a preventable factor. To prevent aggravation of bilateral lymphedema, patients with unilateral lower limb lymphedema should be educated about infection prevention. In addition, the possibility of bilateral progression should be described in patients with lymphangitis, and rapid control of the infection will help prevent progression.

In a comparison of groups A and C for lymph node dissection, the number of patients in group C was very small, at 7, making significance difficult to determine.

Previous studies showed that risk factors for lymphedema after gynecological cancer surgery are age, cancer stage, BMI, vulvar cancer, chemotherapy, and radiation therapy [7, 11, 19-21]. In this study, 63.6% of patients had BMI greater than 23, 44.5% had radiation therapy, 74.5% had chemotherapy, 53.6% had a history of lymphangitis, and 43.6% had genital swelling. In our previous studies on lower limb lymphedema associated with gynecological cancer, BMI, radiation therapy, chemotherapy and lymph node dissection were identified as risk factors [22]. Although BMI and chemotherapy are risk factors for lymphedema, they were not significant for any comparisons conducted in this study, indicating no association with bilateral lymphedema. Age was statistically insignificant even if the criteria were set to 60 and 65 years, and BMI was not significant even if the patients were classified by BMI 25. BMI was obtained by dividing body weight by the square of height and reflected the degree of body fat. Increasing the amount of adipose tissue causes lymphatic dysfunction, which can reduce proximal lymph flow, resulting in lymphedema [23]. However, because muscle mass and bone weight also contribute, BMI and adipose tissue are not directly proportional. Therefore, BMI does not reflect the exact amount of fat a person has. In our study, 5 patients with severe obesity (BMI above 30) were included in the A, B and C groups: 1 person (1.4%) was in group A, 3 (11.1%) in B, and 1 (8.3%) in C. Although findings were not statistically significant, the proportion of patients with severe obesity in groups B and C were considerably higher than the proportion in group A. Therefore, patients with severe obesity who had large amounts of adipose tissues that can cause lymphatic dysfunction can develop bilateral lymphedema. To confirm this finding statistically, a study with a sufficient number of patients with a BMI of 30 or more is needed. Vulvar cancer was not included in our analysis due to a small number of patients. Previous studies have studied risk factors of lymphedema, but we compared bilateral and unilateral lymphedema and identified the factors involved in bilateral lymphedema. We showed that the factors involved in lower limb lymphedema and the factors involved in bilateral lymphedema were only partially consistent.

In this study, cancer stage, genital swelling, and extensive lymph node dissection were identified as factors related to bilateral lower limb lymphedema. Radiation therapy and infection history were identified as factors related to lymphedema progressing from unilateral to bilateral. Patients with unilateral lymphedema who had radiation therapy or had a history of infection were more likely to progress to bilateral lymphedema. These patients should be educated about the possibility of lymphedema progressing from unilateral to bilateral.

All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Kosin University Gospel Hospital (approval number: KUGH 2020-03-006).

Thanks to all the peer reviewers and editors for their opinions and suggestions.

The authors declare no competing interests.