Vulvar cancer is a relatively rare gynecologic malignancy. In 2008, the incidence of vulvar cancer in the Czech Republic was 3.77/100,000, and the mortality rate was 1.73/100,000. Vulvar cancer most frequently occurs in individuals aged between 65 and 84 years (<3% of all vulvar cancers occur in women aged <40 years).1
Approximately 90% of vulvar malignant tumors are squamous cell carcinomas, whereas melanoma tumors make up 2% to 9%.2 The main prognostic factor in vulvar cancer is nodal metastasis, where the extent of its presence correlates with survival. Five-year survival was reported in 90% of patients without inguinal node involvement, 80% in those with 2 or more nodal involvement, and 12% in those with 3 or more nodes with metastasis.3
The generally accepted therapy of early-stage vulvar cancer is wide radical excision, a hemivulvectomy, or modified radical vulvectomy with unilateral or bilateral inguinofemoral lymphadenectomy by the separate incision technique.4 Morbidity from groin dissection is significant. Groin node dissection may be associated with prolonged hospitalization, wound infection, and breakdown. A major source of morbidity (30%–70%) after surgery for the treatment of gynecologic cancer with lymph node removal is lower-limb lymphedema (LLL).5–7 The primary aim of modern vulvar cancer treatment is to minimize treatment-related morbidity. Therefore, an alternative procedure for early stages of vulvar cancer in which the tumor diameter is less than 4 cm, invasion is greater than 1 mm, and no obvious metastatic disease is present is sentinel lymph node biopsy (SLNB). This procedure has been investigated and recently accepted.8,9
Lymphedema occurs when there is reduced drainage of the lymphatic system. Primary lymphedema usually occurs because of congenital abnormality, whereas secondary lymphedema occurs when the lymphatic pathways are impaired by removal of lymph nodes during surgery.7 This increases hydrostatic pressure, which leads to accumulation of extracellular water in the limbs. Late-diagnosed lymphedema tends to persist and may progress to chronic condition.
In lymphedema diagnostics, there is a major problem of the absence of a standard detection method. In the majority of studies, detection by subjective symptoms or detection by measuring the difference in the circumferences of the limbs is used.10–12 A new, objective method, Multifrequency Bioelectrical Impedance Analysis (MFBIA) for LLL, was recently introduced after breast cancer surgery13,14 and after cervical cancer surgery.15 The advantage of this method is its ability to assess body fluid compartments. It was found to have a particularly high sensitivity for lymphedema detection.16,17
The first aim of this study was to prospectively determine the prevalence of secondary LLL after surgical treatment for vulvar cancer with inguinofemoral lymphadenectomy or with a biopsy of the SLNB using objective methods (circumference measurements and MFBIA technique). The second aim was to compare quality of life (QoL) before and 6 months after vulvar surgery in patients who underwent a radical (inguinofemoral lymphadenectomy) or a less radical lymph node procedure using standardized questionnaires.
MATERIALS AND METHODS
After ethical approval from the Faculty Hospital Motol and signing an informed consent, 29 patients undergoing vulvar cancer surgery between July 2007 and December 2009 were included in a prospective, nonrandomized study conducted at the Department of Obstetrics and Gynaecology, 2nd Medical Faculty of Charles University, and University Hospital Motol, Prague, Czech Republic.
Demographic characteristics and data from the surgery (age, weight, height, median of lymph nodes removed, histological type, and tumor grade and stage) were recorded as well as perioperative and postoperative complications.
Patients were examined before and 6 months after surgery by measuring the circumference of the lower limbs and by MFBIA. Moreover, patients were asked to fill in 2 QoL questionnaires: the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the QLQ-CX24 before and 6 months after vulvar surgery.
All patients underwent SLN mapping. Three to 5 hours before surgery, 15 MBq of technetium Tc 99m–labeled colloidal albumin Sentiscint (Mediradiopharma Ltd, Fodor Joszef NCPH, Hungary) was injected into the dermis around the tumor tissues. The blue dye was injected around the tumor 2 to 3 minutes before surgery. Radioactivity was measured quantitatively in the groin lymph nodes just before the skin incision. On entry into the groin, the sentinel nodes were identified by directly observing the afferent, blue lymphatic channel and by using the handheld gamma probe to identify radioactive “hot” nodes. The SLNs were identified as hot, blue, or hot and blue. The first sentinel node was marked as the node with the highest level of activity. Furthermore, SLNs with radioactivity or nodes with a separate afferent blue channel were dissected. These nodes were sent for perioperative histopathologic examination. If the examination indicated a positive result, a complete inguinofemoral lymphadenectomy was performed. The extent of the dissection was limited by the inguinal ligament superiorly, the adductor longus medially, and the sartorius muscle inferolaterally. The primary tumor of the vulva was removed by radical excision or modified radical vulvectomy. Exact surgical techniques have been described in a previous publication from our team.18,19
Twelve patients scheduled for vulvar cancer surgery underwent radical vulvar excision with SLNB and for other nodes with technetium activity (CONS group). In 6 patients, groin surgery was performed unilaterally and in 6 patients bilaterally. The patients with less radical nodal surgery had a tumor diameter less than 4 cm, tumor invasion greater than 1 mm, no metastatic disease, and negative perioperative SLNB. There was no nodal metastasis detected in the definitive histological examination.
Seventeen patients underwent vulvar surgery (13 modified radical vulvectomy and 4 radical vulvar excision) with full bilateral inguinofemoral lymphadenectomy (RAD group). In this group, 13 patients were originally planned for inguinofemoral lymphadenectomy, and 4 patients for a less radical procedure. However, because of a positive result from the perioperative histopathologic examination of the SLN, these patients underwent complete inguinofemoral lymphadenectomy as well. Sentinel lymph node biopsy was performed in all patients in the RAD group, followed by full bilateral inguinofemoral lymphadenectomy. Groin metastasis was detected by SLNB and by final histopathology in 9 patients in the RAD group (52.94%). Ten patients underwent adjuvant radiotherapy, which started minimally 6 weeks after surgery. All these patients were from the RAD group, 9 of whom had lymph node metastasis. Radiotherapy followed a standard treatment protocol. One patient had an involvement of the vagina without nodal metastasis, and hence radiotherapy was planned in this patient already before surgery because of tumor size.
A group of 27 healthy women (control [CONTR] group) was included from our gynecologic department. Lower-limb circumference and MFBIA measurements were performed in all these women.
Four methods were used for detection of lymphedema.
Circumference measurement (LymphV) started at the level of the ankle and then continued every 10 cm proximally for 60 cm. The shape of the lower limb was simplified to 6 cylinders: an average circumference between 2 measured circumferences was calculated, followed by calculating the volume of the cylinder. Finally, by adding the volume of the 6 cylinders, the total volume of the limb was obtained. The accuracy and validity of this procedure have been reported as being equivalent to that of water displacement techniques.20,21 At postsurgery measurement, the patient’s limb volume was compared with the corresponding presurgical value. A patient was diagnosed with lymphedema if the actual limb volume was greater than 110% of limb volume preoperatively.
Multifrequency Bioelectrical Impedance Analysis measurements were made using an Impmeter device (Papouch, Prague, Czech Republic) with the patient in a supine position. Two inductive electrodes were placed 5 cm apart at the ankle and another two 60 cm proximally. Impedance at frequencies of 1, 5, 50, and 100 kHz was recorded. Values R0 (impedance at zero frequency) and Ri (impedance at infinity) were estimated using regression analysis. An interpretation was used according to Cornish et al13 using impedance at zero frequency (R0) and according to Watanabe et al22 using a ratio of impedance at infinity (Ri) and impedance at zero frequency (Ri/R0). SD of R0 for the MFBIA measurement was calculated from a single MFBIA measurement in the CONTR group.
Using MFBIA, lymphedema was diagnosed by 2 modifications: when the actual R0 is greater than 1.645 SD from the R0 preoperatively (LymphR0 SD)13 and when the actual Ri/R0 is greater than 140% of the preoperative Ri/R0 (LymphRi/R0).22
Lymphedema was diagnosed by patient self-reports (LymphSelf) if the patients were observed to have “lower-limb swelling or edema that occurred after surgery.”
Before and 6 months after vulvar surgery, all patients completed 2 QoL questionnaires: EORTC QLQ-C30 and EORTC QLQ-CX24. In both the CONS and RAD groups, postoperative results were compared with preoperative results. Because a vulva-specific EORTC questionnaire was not available at the initiation of this study, we used the QLQ-CX24, which was designed for cervical cancer patients who often have similar problems to those who have undergone vulvar cancer surgery. The EORTC QLQ-C30 version 3.0, a cancer-specific questionnaire, consists of 5 functional scales, a global health status, and 9 symptom scales. The global health status correlates significantly with all of the functional and symptom scales.23 For the functional and global QOL scales, a higher score indicates a better level of functioning; concerning the symptom scales, a higher score indicates a worse level of functioning. The EORTC QLQ-CX24 questionnaire consists of 3 multi-item scales and single-item scales.24,25 Validation of this questionnaire into the Czech language was performed by our group.26
A χ2 test of independence in the contingency table (or Fisher exact test for small theoretical counts in the table) was used to compare histological type and grade of tumors. An analysis of variance was performed to compare age, height, weight, and limb volumes between the CONS and RAD groups. Prevalence of lymphedema 6 months after surgery was analyzed by Fisher exact test. Prevalence of lymphedema by all 4 methods (LymphV, LymphR0 SD, LymphRi/R0, LymphSelf) was calculated at 6 months after surgery, whereas sensitivity and specificity of all 3 methods (LymphR0 SD, LymphRi/R0, LymphSelf) were analyzed against the circumference method (LymphV) as a standard method. Risk factors (eg, age >60 years, body mass index >30 kg/m2, and adjuvant radiotherapy) were evaluated. A 2-sample t test was performed to evaluate differences between QoL scores in the CONS and RAD groups and between both groups 6 months after the surgery. In addition, a paired t test was done to study differences between time points. All statistical analyses were conducted using SAS 9.1 Software (SAS Institute Inc, Cary, NC).
Data from the EORTC QLQ-C30 and QLQ-CX24 questionnaires were analyzed in accordance with the EORTC scoring manuals.23,24
A demographic description of patients with cancer (CONS and RAD groups) and the CONTR group is given in Table 1, together with the distribution of histological type, grade, and stage of the tumor. Statistically significant differences between the CONS and RAD groups were found in the patients’ age, International Federation of Gynecology and Obstetrics (FIGO) stage of the tumors, and the number of lymph nodes dissected.
There were no cases of perioperative complications. However, 1 case of an infectious complication and 2 cases of repeated surgery for dehiscence of the wound after lymphadenectomy were observed 1 month after surgery in the RAD group.
Using CONTR group, an SD of R0, necessary for MFBIA testing, was found: 46.89 for the right leg and 44.08 for the left leg.
Nine patients with LLL were detected using the circumference method 6 months after surgery. In the CONS group, there were 2 unilateral and 1 bilateral LLLs (25%); in the RAD group, there were 2 unilateral and 4 bilateral LLLs (37.5%). The difference between groups, however, was not statistically significant (P = 0.69). By the self-reporting method of lower-leg swelling, there were 2 cases of LLL in the RAD group and none in the CONS group.
The number of lymphedemas detected by MFBIA is presented in Table 2. Sensitivity and specificity of MFBIA and subjective symptoms against circumference measurement are given in Table 3. Higher lymphedema prevalence was found with the MFBIA method as compared with the circumference measurement or patient self-reports.
None of the risk factors was found to be statistically significant: age older than 60 years (P = 1.0), body mass index (P = 0.69), and adjuvant radiotherapy (P = 0.24).
In the EORTC QLQ-C30, a difference was noted in both operated groups in the mean value of global health status 6 months after surgery. Moreover, 6 months after surgery, physical and role functioning and fatigue were reported to worsen more often in patients after inguinofemoral lymphadenectomy (RAD group). When comparing both groups 6 months after surgery, the RAD group had significantly worse parameters in social functioning, fatigue, and dyspnea. In addition, the RAD group exhibited marginally worse lymphedema. Quality-of-life scores are summarized in Tables 4 and 5. Statistical analysis could not be performed for some questions, however, because too few patients responded (marked as not applicable).
In our study, lymphedema was detected by circumference measurement in 25% of the patients in the CONS group and in 37.5% of the patients in the RAD group 6 months after surgery. Although the difference was not statistically significant, the trend in favor of the less radical groin procedure was obvious. With further incorporation of the dissection of only SLNs with the highest radioactivity, rather than dissecting all radioactive lymph nodes, the difference should be even more pronounced. In a study of van der Zee et al,9 lymphedema was noted in 1.9% of the patients with SLNB and in 25.2% of the patients with inguinofemoral lymphadenectomy. Reports on the prevalence of lymphedema after vulvar cancer surgery varies widely (from 0% to 70%).5–7,27–29 In a retrospective study, the Gynecologic Oncology Group described the use of superficial groin node dissection with modified radical hemivulvectomy in 121 patients with T1 lesions, reporting lymphedema in 19%.29 In another retrospective study of 415 women over a 45-year period, Cavanagh et al27 reported that only 8.6% of the women developed LLL after inguinofemoral lymphadenectomy for vulvar cancer. In the retrospective study by Ryan et al7 composed of 44 women, 59% developed LLL after vulvectomy and lymph node removal. Most of the studies in the literature were designed as retrospective studies or did not detect LLL using objective measurements. Because of the rare incidence of vulvar cancer, the majority of conclusions are often based on small groups of patients. Another potential factor to account for the divergence of prevalence of lymphedema is the use of different methods of lymph node removal.
When MFBIA was used, a higher prevalence of postoperative lymphedema was found as compared with circumference measurement. This finding can be explained by the sensitivity of the MFBIA method; that is, it is able to detect changes in extracellular water volume before its clinical manifestation. Because the specificity and sensitivity of the MFBIA method in this study are lower than we expected, it is necessary to continue to monitor the patients for a longer time. In this respect, Cornish et al30 detected lymphedema by MFBIA up to 10 months before the condition could be clinically detected.
Several risk factors for the development of postoperative lymphedema have been reported in the literature.5 In our study, we tested 3 risk factors (age >60 years, body mass index >30 kg/m2, and postoperative radiation), none of which was found significant for LLL development. The same conclusion regarding age (>65 years) and postoperative radiotherapy was found in a study of Gaarenstroom et al31 in 101 patients after modified radical vulvectomy and complete inguinofemoral lymphadenectomy. Radiotherapy to the groin seems to have less potential of causing lymphedema than expected. A randomized trial with 114 patients after radical vulvectomy and inguinal lymphadenectomy compared postoperative pelvic and groin radiation with pelvic node dissection and found a similar prevalence of chronic lymphedema.32 In a review comparing radiotherapy and surgery to the groin, a relative risk of 0.06 (95% confidence interval, 0.00–1.03) in favor of the radiotherapy group was reported.33 Thus, it seems that, in vulvar cancer, lymph node dissection is the major cause of lymphedema, but there is insufficient evidence that patients after radiation for vulvar cancer are at a higher risk of LLL.
Concerning the EORTC questionnaires in our study, the global health status of patients 6 months after both types of inguinal surgery was not significantly worse than before surgery. When comparing both groups, statistically significant differences were found in social functioning, fatigue, and dyspnea. In a study (GROINSS-V) in which patients underwent either SLNB or inguinofemoral lymphadenectomy, no differences were found between the groups in QoL as measured by the EORTC QLQ-C30 questionnaire, except for financial difficulties and lymphedema, which were reported more often among patients who underwent inguinofemoral lymphadenectomy.34 The focus of most QoL studies in relation to vulvar cancer has been sexual functioning. As might be expected, the QoL domain is significantly reduced in vulvar cancer patients. There is growing evidence that women who undergo surgical treatment for vulvar cancer are at a high risk for sexual dysfunction, show dissatisfaction with partner relationship, and have psychological difficulties. Factors associated with posttreatment sexual dysfunction include older age, poor overall well-being, history of depression, anxiety, and excision size of the vulvar malignancy.35 In a study of 41 women 3 months after vulvectomy, a high disturbance in body image and sexual dysfunction was reported, especially hypoactive sexual and aversion disorders.36 Depression and advanced age were risk factors for sexually active women to discontinue sexual intercourse after surgery. There was no correlation between sexual dysfunction and type of vulvar surgery.
Several differences between the RAD and CONS groups need to be noted. This was a prospective, nonrandomized trial. The RAD group included patients with positive lymph nodes, which means that patients in this group have a higher mean age and a higher FIGO stage. The median of lymph nodes removed during less radical groin surgery (SLN and other nodes with technetium activity) in our study was 2.5 per groin and 4.5 during inguinofemoral lymphadenectomy. This prospective study was initiated in 2007, before the official acceptance of SLN mapping as an alternative to inguinofemoral lymphadenectomy.8 Therefore, we removed not only the SLNs but all nodes with radioactivity, which resulted in a small difference between the RAD and CONS groups. Moore et al28 reported an average of 2 SLNs per groin on each side in SLN dissection of 35 patients with vulvar cancer.
Although not statistically significant, higher limb volume was found in the CONS group before surgery. Lower-limb lymphedema detection was not affected by this, as for the diagnosis, a difference of volume before and after surgery of each leg separately was used.
Higher lymphedema score in the QLQ-CX24 questionnaire in CONS group shows the limitation of subjective methods, when a positive answer to the question about either leg’s swelling is evaluated as lymphedema presence in the majority of questionnaires. This finding emphasizes the need to use objective methods for lymphedema detection, which should preferably be done before surgery.
There are some limitations of our study. The size of the groups of patients is small because of low prevalence of vulvar cancer and because it was not a multicentric study. Thus, the study was not powered to detect a difference in sensitivity and specificity of MFBIA method and circumference measurement. On the other hand, the differences in QoL were statistically significant even in such a small group of patients and even with a relatively small difference in the number of dissected lymph nodes in both groups.
Lower radicality in inguinofemoral lymphadenectomy shows a trend toward lower morbidity and significantly improves QoL. The prevalence of lymphedema was 31% when using an objective measurement (ie, measurements of the circumference of the limbs). Detection of lymphedema based on subjective evaluations proved to have an unsatisfactory sensitivity. Less radical surgery showed objectively better results in QoL.
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