C-reactive protein serum levels are closely associated with lymph node status, but not with prognosis in patients with vulvar cancer

OBJECTIVE: To evaluate whether C-reactive protein (CRP) serum levels can be used as prognostic parameter in patients with vulvar cancer. STUDY DESIGN: CRP serum levels were measured at the time of first diagnosis of squamous cell vulvar cancer. Sixty-seven patients were enrolled; results were correlated to clinical data. RESULTS: Mean CRP serum levels in patients with vulvar cancer were 0.8 (0.80)mg/dL. CRP serum levels were significantly associated with lymph node involvement (p=0.003), but not with tumor stage (p=0.03), histological grade (p=0.86) and patients' age (p=0.64). Univariate analysis showed lymph node involvement, tumor stage and histological grade, but not CRP serum levels and patients' age to be associated with overall survival. A multivariable analysis determined only lymph node involvement as independent prognostic parameter for disease-free interval and overall survival. CONCLUSION: CRP serum levels are closely associated with lymph node status but cannot be used as prognostic parameter in patients with vulvar cancer.     

Squamous cell carcinoma antigen serum levels as prognostic parameter in patients with early stage vulvar cancer

OBJECTIVE: To determine whether SCC-Ag serum levels can be used as a prognostic parameter in surgically treated early stage vulvar cancer. METHODS: SCC-Ag serum levels were measured preoperatively in 61 surgically staged patients with squamous cell vulvar cancer (UICC pT1 and pT2). Results were correlated to clinical data. RESULTS: Mean (standard deviation) SCC-Ag serum levels in patients with vulvar cancer were 1.5 (1.99) ng/mL. SCC-Ag serum levels were significantly higher in patients with pT2 vulvar cancer (2.2 [2.6] ng/mL) compared with patients with pT1 vulvar cancer (1.0 [1.2] ng/mL, P = 0.034). SCC-Ag serum levels were not associated with lymph node involvement (P = 0.1), tumor grade (P = 0.6), and patients' age (P = 0.5). Multivariate Cox regression models considering tumor stage, lymph node involvement, patients' age, and SCC-Ag serum levels as covariates showed that lymph node involvement (P = 0.04 and P = 0.01) and tumor stage (P = 0.006 and P = 0.009), but not SCC-Ag serum levels (P = 0.8 and P = 0.6), and patients' age (P = 0.08 and P = 0.22) are prognostic factors for disease-free and overall survival, respectively. CONCLUSION: SCC-Ag serum levels cannot be used as an additional prognostic parameter in patients with surgically treated early stage vulvar cancer.     

The impact of plasma fibrinogen levels on patients with vulvar cancer

Objective

To investigate the association between plasma fibrinogen levels and clinico-pathological parameters of patients with vulvar cancer and to determine their value as prognostic parameters.

Study design

In this retrospective study, we evaluated pretreatment plasma fibrinogen levels in 120 patients with invasive squamous cell vulvar cancer and correlated them with clinico-pathological parameters and patients’ survival.

Results

Pretreatment plasma fibrinogen levels were directly associated with tumor stage (pT1a vs. pT1b vs. pT2 vs. pT3-4, p = 0.001), lymph node involvement (pN0 vs. pN1, p = 0.04), and histological grade (G1 vs. G2 vs. G3, p = 0.03), but not with patients’ age (≤70 years vs. >70 years, p = 0.6). In a multivariate survival analysis, tumor stage (p = 0.006/p = 0.02) and lymph node involvement (p < 0.001/p < 0.001), but neither histological grade (p = 0.2/p = 0.9) nor plasma fibrinogen levels (p = 0.6/p = 0.6) were associated with disease-free and overall survival, respectively. In a multivariate analysis, patient's age (≤70 years vs. >70 years) was associated with overall survival (p = 0.03) but not with disease-free survival (p = 0.1).

Conclusion

Pretreatment plasma fibrinogen levels were directly associated with tumor stage, lymph node involvement and histological grade. Although we could demonstrate a prognostic value of pretreatment plasma fibrinogen levels on survival, we were unable to establish fibrinogen as an independent prognostic parameter in patients with vulvar cancer.     

Long-term follow-up of vulvar cancer patients evaluated with sentinel lymph node biopsy alone

Objective

The objective of this study was to examine SLN evaluation alone in women with squamous cell carcinoma (SCC) of the vulva and evaluate the inguinal recurrence and complication rates.

Methods

An IRB approved prospective study enrolled patients with SCC of the vulva. Peritumoral injection of Tc-99 sulfur colloid and blue dye was used to identify SLNs intraoperatively. Patients with negative SLN for metastasis were followed clinically without further treatment. Patients with metastasis to a SLN underwent full groin node dissection followed by standard treatment protocols.

Results

A total of 73 women were enrolled onto protocol with 69 patients undergoing SLN dissection. Mean age was 66.9 years (range: 29–91) with 47 stage I, 12 stage II, 9 stage III, 2 stage IV and 3 unstaged patients. SLN dissections were successful in 63 patients. Of the 111 groins evaluated with a SLN dissection 93% had a SLN identified with an average of 2 SLN per groin. There were 92 groins with negative SLN and 11 groins with positive SLN. 57 patients had negative SLN and underwent conservative management with the median follow-up of 58.3 months. Three patients experienced groin recurrences (2 unilateral, 1 bilateral) for a recurrence rate of 5.2% (3/57). The complication rate for the inguinal incisions was 17.5% (1 cellulitis, 1 abscess, 2 lymphoceles, 5 lymphedema and leg pain).

Conclusions

Isolated SLN dissection alone has a low inguinal recurrence rate with decreased complications and should be considered as an option for women with SCC of the vulva.     

Identification of inguinofemoral lymph node metastases by methylation markers in vulvar cancer

Objective

Lymph node status in early-stage vulvar cancer can be accurately assessed by the sentinel-node (SN) procedure. Molecular techniques, such as DNA-methylation assay, might improve SN assessment. In this study, we selected methylation markers for vulvar cancer and determined if these methylation markers were suitable for lymph node assessment.

Methods

We performed methylation specific PCR on DNA isolated from primary tumors, metastatic lymph nodes, and negative lymph nodes from twenty vulvar cancer patients using the following genes: P16INK4a, MGMT, TWIST1, CADM1, TERT, and TFPI2. For P16INK4a and MGMT immunohistochemistry was performed on primary tumors and metastatic lymph nodes in order to explore intratumor heterogeneity in gene expression patterns.

Results

TERT was methylated in all vulvar cancers, P16INK4a in 13/20, TFPI2 in 12/20, CADM1 in 11/20, MGMT in 9/20, and TWIST1 in 7/20. A panel of three methylation markers (P16INK4a, TERT and TFPI2) reached a sensitivity of 67% and specificity of 100% for detection of metastatic lymph nodes. Immunohistochemistry showed intratumor heterogeneity for expression of P16INK4a and MGMT in respectively 55% and 45% of primary tumors.

Conclusions

Our study shows methylation for one or more methylation markers in all vulvar cancers. Despite a specificity of 100% our panel of three methylation markers had only moderate sensitivity for metastatic lymph node detection, thereby limiting its applicability for lymph node assessment. Intratumor heterogeneity for expression of P16INK4a and MGMT may reflect intratumor heterogeneity for methylation patterns and thereby in general explain the moderate sensitivity of our marker panel for detection of metastases.     

The inflammation-based modified Glasgow Prognostic Score in patients with vulvar cancer

Objectives

To evaluate the prognostic potential of the modified Glasgow Prognostic Score (mGPS), known to reflect the degree of tumor-associated inflammation and cachexia, in patients with vulvar cancer.

Study design

We included 93 consecutive patients with vulvar cancer into our study. As previously published, the pre-therapeutic mGPS was calculated as follows: patients with elevated C-reactive protein (CRP) serum levels (>10 mg/L) and hypoalbuminaemia (<35 g/L) were allocated a score of 2, patients with elevated CRP serum levels without hypoalbuminaemia were allocated a score of 1, patients with normal CRP serum levels with or without hypoalbuminaemia were allocated a score of 0. The mGPS was correlated with clinico-pathological parameters. The association between mGPS and prognosis was evaluated by univariate and multivariate survival analysis.

Results

Mean (SD) pretreatment CRP and albumin serum levels were 9.5 (9.6) mg/L and 41.4 (5.3) g/L, respectively. mGPS was associated with tumor stage (p = 0.01), but not with lymph node involvement (p = 0.4), histological grade (p = 0.8), and patients’ age (p = 0.7). In univariate analyses, mGPS (p = 0.006, p = 0.001), tumor stage (p < 0.001, p < 0.001), lymph node involvement (p < 0.001, p < 0.001), and patients’ age (p = 0.04, p = 0.007), but not histological grade (p = 0.1, p = 0.3) and year of surgery (1995–2001 vs. 2002–2008, p = 0.7, p = 0.3) were associated with disease-free and overall survival, respectively. In a multivariate analysis, tumor stage (p = 0.01, p = 0.02) and lymph node involvement (p < 0.001, p = 0.001), but not mGPS (p = 0.7, p = 0.8), patients’ age (p = 0.6, p = 0.4), histological grade (p = 0.2, p = 0.1), and year of surgery (p = 0.4, p = 0.8) were associated with disease-free and overall survival, respectively.

Conclusions

Despite being associated with prognosis in a univariate analysis, mGPS cannot be used as an independent inflammation-based predictor for survival in patients with vulvar cancer.     

血清胆固醇水平对宫颈癌患者预后的影响

目的:探讨治疗前血清胆固醇水平对宫颈癌患者预后的影响。方法:回顾分析2016年1月1日至2016年12月31日四川省肿瘤医院妇科肿瘤中心收治的277例宫颈癌患者的临床病理资料和随访记录。绘制ROC曲线,评价治疗前血清胆固醇对患者预后的预测效果。分析患者临床病理资料与血清胆固醇水平的关系。应用Kaplan-Meier法绘制生存曲线,建立Cox比例风险模型分析患者预后影响因素。结果:血清胆固醇水平预测DFS、OS的临界值分别为4.875mmol/L、4.605mmol/L。Cox比例风险模型单因素及多因素分析显示,治疗前血清胆固醇水平是影响宫颈癌患者DFS及OS的危险因素。结论:治疗前血清胆固醇水平可作为宫颈癌患者预后风险评价指标。     

Groin recurrence in patients with vulvar cancer with negative nodes on superficial inguinal lymphadenectomy

OBJECTIVE: The objective of this study was to investigate the cause of groin recurrence in patients with vulvar cancer who had negative nodes in their superficial inguinal lymphadenectomy (SIL) specimens. METHODS: The records of patients with vulvar cancer treated at M. D. Anderson Cancer Center between 1986 and 1997 were reviewed to identify patients with squamous histology, clinical and surgical stage I or II, depth of invasion greater than 1 mm, and primary treatment consisting of radical wide excision and SIL. One hundred four patients met these criteria. Among these, nine experienced recurrent disease that involved one or both of the groins. All of the original hematoxylin and eosin (H&E)-stained slides were reviewed by one pathologist (AM). Then, each paraffin block containing nodal tissue was recut at 40 microm intervals to obtain five sections for H&E staining and two unstained sections to be used for cytokeratin immunostaining if necessary. RESULTS: The median age at diagnosis and primary surgery was 65 years and the median depth of invasion was 4 mm. Seven patients underwent bilateral, and two underwent unilateral, groin dissections. The median number of lymph nodes removed per groin was seven. The median time to recurrence was 22 months. A total of 785 additional H&E-stained slides were prepared and examined at 100x and 400x magnification. No micrometastases were identified, and there were no other suspicious findings. Therefore, immunohistochemical staining was not performed. At recurrence, one patient had a biopsy only, and eight had attempted surgical resection. In two patients, tumor was identified in fibroadipose tissue only; no lymph nodes were identified. Among the other six patients, the median number of lymph nodes resected at the time of the recurrence was five (range 1 to 10). At last report, six patients had died and three were alive and free of disease. Median follow-up for survivors was 63 months (range 42 to 71). CONCLUSION: These data strongly suggest that groin relapse in patients with negative nodes on SIL is caused by metastatic disease in unresected inguinal nodes. SIL as performed on the patients in this study did not eliminate all sites of nodal metastasis.     

Radioguided sentinel lymph node detection in vulvar cancer

Lymph node status is the most important prognostic factor in vulvar cancer. Histologically, sentinel nodes may be representative of the status of the other regional nodes. Identification and histopathologic evaluation of sentinel nodes could then have a significant impact on clinical management and surgery. The aim of this study was to evaluate the feasibility and diagnostic accuracy of sentinel lymph node detection by preoperative lymphoscintigraphy with technetium-99 m-labeled nanocolloid, followed by radioguided intraoperative detection. Nine patients with stage T1, N0, M0, and 11 patients with stage T2, N0, M0 squamous cell carcinoma of the vulva were included in the study. Only three cases had lesions exceeding 3.5 cm in diameter. Sentinel nodes were detected in 100% of cases. A total of 30 inguinofemoral lymphadenectomies were performed, with a mean of 10 surgically removed nodes. Histological examination revealed 17 true negative sentinel nodes, 2 true positive, and 1 false negative. In our case series, sentinel lymph node detection had a 95% diagnostic accuracy, with only one false negative. Based on literature evidence, the sentinel node procedure is feasible and reliable in vulvar cancer; however, the value of sentinel node dissection in the treatment of early-stage vulvar cancer still needs to be confirmed.     

Multimodal surgical guidance towards the sentinel node in vulvar cancer

Introduction

Conventional sentinel node (SN) mapping is performed by injecting a radiocolloid followed by lymphoscintigraphy (and SPECT/CT imaging). An extra intraoperative injection with blue dye can then allow for optical identification of the SN. In order to improve the current clinical standard, the hybrid tracer indocyanine green (ICG)-^99mTc-nanocolloid was introduced, a tracer that is both radioactive and fluorescent. This feasibility study aimed to evaluate the value of a multimodal-based SN biopsy in vulvar cancer.

Materials and methods

Fifteen patients with vulvar cancer (29 groins) scheduled for SN biopsy were peritumorally injected with ICG-^99mTc-nanocolloid followed by lymphoscintigraphy and SPECT/CT imaging to identify the SNs. In thirteen patients, shortly before the start of the operation, blue dye was intradermally injected around the lesion. SNs were harvested using a combination of radiotracing, fluorescence imaging, and optical blue dye detection. A portable gamma camera was used before and after SN excision to confirm excision of the preoperatively defined SNs.

Results

Preoperative lymphoscintigraphy and SPECT/CT imaging visualized drainage to 39 SNs in 28 groins. During the operation, 98% (ex vivo 100%) of the SNs were radioactive. With fluorescence imaging 96% of the SNs (ex vivo 100%) could be visualized. Only 65% of the SNs had stained blue at the time of excision.

Conclusion

ICG-^99mTc-nanocolloid can be used for preoperative SN identification and enables multimodal (radioactive and fluorescent) surgical guidance in patients with vulvar cancer. The addition of fluorescence-based optical guidance offers more effective SN visualization compared to blue dye.     

Impact of the new FIGO 2009 staging classification for vulvar cancer on prognosis and stage distribution

Objective

In 2009, FIGO modified staging of vulvar cancer — the performance of the new classification relative to the prior system has not been assessed. We sought to investigate the impact of the 2009 FIGO vulvar cancer staging system on stage distribution and prognostic ability of the 2009 sub-stage classifications in a large cohort of uniformly staged cases with long-term followup.

Methods

Patients undergoing surgery for vulvar cancer were identified from 2 institutions (Mayo Clinic and Medical University, Gdansk, Poland) using a similar surgical approach. Inclusion criteria required primary surgery for invasive vulvar cancer for cases with > 1 mm invasion with complete inguinal/femoral lymphadenectomy. The technique of inguinofemoral node dissection used in both institutions was designed to remove both superficial and deep inguinofemoral nodes. A retrospective review was performed and all cases were assigned stage using the 1988 and 2009 FIGO systems after reviewing pathology slides. Cause-specific survival (CSS, death due to cancer) was estimated using the Kaplan-Meier method and compared using the Cox proportional hazards model t for the first 10 years after surgery.

Result

A total of 468 patients met inclusion criteria. Thirty-one percent (n = 155) were down-staged, and 1 case up-staged using 2009 staging. The new system fails to effectively separate 10-yr CSS for stage I and II cases (p = 0.52), while FIGO 1988 failed to separate stages II and III (p = 0.41). We observed a difference in survival for stage I and II cases based on tumor diameter. For smaller stage II lesion (≤ 4 cm vs. > 4 cm) we observed no difference in survival compared to all stage IB cases (p = 0.25) Considering node positive disease, patients with 2009 FIGO stages ΙΙΙA, ΙΙΙB, and ΙΙΙC were not significantly different in terms of CSS (p = 0.17). However, CSS approached significance between patients with extracapsular vs. intracapsular disease (p = 0.072). For stages IIIA and IIIB (excluding extracapsular spread, IIIC), we observed that the number of positive nodes and diameter of lymph node metastasis were not significantly associated with CSS. When comparing bilateral nodal involvement vs. unilateral cases with at least 2 involved nodes, we found no statistical difference in CSS (p = 0.30).

Conclusion

This is the largest cohort study to evaluate the effect and prognostic performance of the new FIGO vulvar cancer staging system. The new staging does not stratify survival between stages I and II and reduces CSS in stage I cases. Our results suggest that lesion size in node negative cases is an important prognostic variable that could be addressed in future staging classifications. Among the node positive cases, the current classification results in slight differences in CSS, primarily between intra- and extra-capsular disease and not according to the number of positive nodes and lymph node metastasis diameter. Finally we observe that bilateral nodal disease does not appear to impact CSS, justifying it being omitted from the 2009 staging system and that separating node positive (2009 stage III) from node negative (2009 stage II) cases is justified.     

A review of complications associated with the surgical treatment of vulvar cancer

Objective

The mainstay of treatment for most vulvar malignancies is surgery to the vulva with lymphadenectomy to the inguino-femoral areas, plus radiotherapy or/and chemotherapy for locally advanced, or recurrent disease. Treatment is associated with significant physical, sexual, and psychological morbidity. The high morbidity rate has resulted in a continuing shift in treatment paradigms that focus on treatments that reduce morbidity without compromising cure rates. This paper reviews the complications associated with contemporary surgical treatment for vulva cancer and discusses preventative strategies.

Methods

A review of the English literature was undertaken for articles published between 1965 and August 31, 2012 to identify articles that assessed complications resulting from surgery to the vulva or groins in patients with vulva cancer. Two independent researchers selected and qualitatively analyzed the articles using a predetermined protocol.

Results

The heterogeneity of articles and differences in definitions and outcomes made this unsuitable for meta-analysis. Most studies advocated for change in surgical technique to reduce complications associated with inguino-femoral lymphadenectomy and surgery to the vulva, with varying success. The most effective means of preventing complications is by omitting systematic lymph node dissection. This can be achieved safely through sentinel lymph node biopsy. Saphenous vein sparing, VTE prophylaxis, the use of flaps and grafts, and preoperative counseling are additional ways to decrease morbidity.

Conclusion

Despite technical advances, complications following surgical treatment for vulva cancer remain high. More research, particularly multi centered randomized controlled trials to improve the quality of evidence and studies that focus on complications as an outcome measure and analyze individual surgeon complication rates, are needed. Measures also need to be standardized throughout the gynecologic oncology community to allow for better comparison between studies.     

EGFR expression is associated with groin node metastases in vulvar cancer, but does not improve their prediction

OBJECTIVES: High morbidity of elective inguinofemoral lymphadenectomy in early stage vulvar cancer patients urges the need for defining a group of low-risk patients in whom inguinofemoral lymphadenectomy can be safely omitted. Aim of the study was to evaluate whether in addition to 'classic' clinicopathological factors determination of EGFR expression in vulvar cancer can be helpful in defining such a 'low-risk' group. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples of 197 surgically treated T1/2 patients were collected in a Tissue Micro Array (TMA). On this TMA, immunohistochemistry for EGFR was performed. Logistic regression analyses were performed including histopathological characteristics with the presence of nodal metastases as outcome. A predictive model was constructed, and absolute risks were calculated. RESULTS: EGFR expression was present in 68% of the vulvar tumors and related to the presence of lymph node metastases (OR 2.12, 95% CI 1.09-4.10). Our predictive model with only clinicopathological factors was able to define a group of patients with a likelihood of absence of lymph node metastases of 13% (95% CI 5-36), which could be decreased to 6% (95% CI 0-29) after inclusion of EGFR expression (p=0.07). CONCLUSIONS: EGFR expression is present in the majority of vulvar tumors and is associated with groin node metastases in vulvar cancer. Current classic clinicopathological predictive factors for inguinofemoral lymph node metastases with or without EGFR analysis are not strong enough for identification of "sufficiently low" risk T1/2 vulvar cancer patients. Our predictive model approach however is excellent for evaluation of new cell biological parameters, associated with clinical outcome.     

Polymorphisms of the endothelial nitric oxide synthase gene in women with vulvar cancer

Objective. Nitric oxide (NO) is involved in angiogenesis and tumor growth. We attempted to establish an association between two polymorphisms of the endothelial nitric oxide synthase (NOS3) gene and vulvar cancer.Methods. We used peripheral vanous blood sampling, DNA extraction, and polymerase chain reaction (PCR) and pyrosequencing to genotype 68 women with vulvar cancer and 227 healthy Caucasian women for the presence of the intron 4 27-bp-repeat [NOS3*A] and exon 7 Glu298Asp polymorphisms.Results. The presence of a polymorphic NOS3*A allele (26.2% vs. 24.6%; OR: 1.01; 95% CI: 0.6–2.0; P = 0.9) or a polymorphic NOS3 exon 7 Glu298Asp allele (41.2% vs. 53.7%; OR: 0.6; 95% CI: 0.3–1.0; P = 0.09) was not associated with vulvar cancer. Within the vulvar cancer group, the presence of a polymorphic NOS3*A or a polymorphic NOS3 exon 7 Glu298Asp allele was not associated with clinico-pathological parameters such as advanced tumor stage, groin lymph node involvement, tumor grading, and age at diagnosis. Survival analysis demonstrated that the presence of a polymorphic NOS3*A allele was associated with a significantly reduced disease-free survival time (P = 0.03), whereas the presence of the polymorphic NOS3 exon 7 Glu298Asp allele was not associated with disease-free survival (P = 0.5).Conclusions. We are the first to report on NOS3 polymorphisms in vulvar cancer. We found that allelic variation within intron 4, but not within exon 7 of NOS3, influences the length of disease-free survival, but not the biological phenotype of vulvar cancer.     

Evaluation of sentinel lymph nodes in vulvar,endometrial and cervical cancers

Sentinel lymph node (SLN) biopsies are a sensitive tool in evaluating lymph nodes for multiple cancers, and in some diseases they decrease morbidity in both the short- and long-term. SLN detection in gynecologic malignancies has been studied extensively over the past decade. We review the current literature on SLN dissection in vulvar, endometrial and cervical cancers. Large, well-designed trials in each of the three types of cancer have demonstrated high sensitivity and low false-negative rates when SLN biopsy is performed in the correct patients and with an appropriate technical approach. In all of these cases the addition of ultra-staging to conventional pathology yields increased detection of micrometastatic disease. Biopsy of the sentinel nodes is feasible and safe in early vulvar malignancies, with multiple studies describing low recurrence rates in those women who have with negative SLNs. There does not appear to be a survival benefit to lymphadenectomy over SLN biopsy and quality of life is improved in women undergoing SLN biopsy. Optimal treatment strategies for women with positive nodal biopsies, particularly in cases with micrometastatic disease, remain unclear. Multiple large studies investigating the utility of SLN biopsy in endometrial malignancy have found that sentinel nodal status is a reliable predictor of metastases in women with low-risk disease. Prospective studies are ongoing and suggest sentinel nodal detection may soon become widely accepted as an alternative standard of care for select cases of endometrial cancer. In cervical cancer, SLN biopsy is accurate for diagnosing metastatic disease in early stage tumors (≤ 2 cm diameter or stage ≤ IB2) where the risk of metastasis is low. It is unknown if women who undergo SLN biopsy alone will have different survival outcomes than women who undergo complete lymphadenectomy in these cases. In a specific population of women with vulvar cancer, SLN dissection is an effective and safe alternative to complete dissection. It can be offered as an alternative management strategy in these women. In women who do undergo SLN biopsy, it is associated with improved quality of life. Promising evidence supporting the utility of SLN dissection in endometrial and cervical cancer continues to emerge, and it may soon become a reasonable option for select patients. However, continued research and refinement of appropriate patient selection and long-term follow-up are necessary.     

Adjuvant treatment in cervical,vaginal and vulvar cancer

Primary surgical management is successful as the sole therapeutic modality in the majority of women with early-stage cervical, vaginal and vulvar cancer, but the presence of certain risk factors in the surgico-pathological specimen indicates a poorer prognosis. Adjuvant treatment can improve overall survival in such cases. Important risk factors in cervical cancer include intermediate-risk factors (large tumor size, deep cervical stromal invasion, lymph-vascular space invasion) and high-risk factors (positive or close margins, lymph nodes, or parametrial involvement). In vulvar cancer, positive margins and lymph nodes are the two most important factors for adjuvant therapy. Radiation therapy has been the mainstay of adjuvant therapy in these cancers, supplemented by chemotherapy. Recent advances have witnessed the inclusion of newer therapeutic modalities such as immunotherapy. This review addresses the current status of various adjuvant therapeutic modalities for these gynecological cancers.     

The role of preoperative ultrasound evaluation of inguinal lymph nodes in patients with vulvar malignancy

Objectives

Inguinal lymphadenectomy in vulvar malignancies is associated with significant morbidity, especially in patients over 70 years old. Under certain conditions, surgical guidelines recommend biopsy and evaluation of the sentinel node in early vulvar cancer. The purpose of our study is to evaluate ultrasonography as a predictor of inguinal lymph node involvement.

Methods

A retrospective study was performed with 60 patients who had vulvar malignancies (92% of which were squamous cell carcinomas) and who were treated at our hospital between 2002 and 2012. The patients ranged in age from 35 to 89 years, with a median age of 76 years. In total, 118 groin scans were retrospectively evaluated for sonographic evidence of lymph node involvement (i.e., absence of fatty hilum, irregular shape, cortical region diameter and vascularization pattern). The results were then compared with histopathologically confirmed lymph node status.

Results

Histopathologically confirmed lymph node status was available for 107 of the inguinal nodes examined by ultrasound, and lymph node metastases were found in 38 (35.5%) cases. The presence or absence of inguinal lymph node metastases was correctly identified by sonography in 92 (86.0%) of the scanned areas. Sensitivity was 76.3%, specificity was 91.3%, and positive and negative predictive values were 82.9% and 87.5%, respectively.

Conclusions

Ultrasonography of the inguinal lymph nodes showed a relatively high sensitivity and specificity for predicting inguinal tumor metastases. However, our results indicate that surgical lymph node staging is still needed to precisely determine inguinal lymph node status in vulvar cancer, especially because a missed lymph node-metastasis is often fatal.     

FOXP3+ regulatory T-cells are abundant in vulvar Paget's disease and are associated with recurrence

Objective.

To characterize clinical features of vulvar Paget's disease, and examine the quantity of immunosuppressive regulatory T-cells in vulvar Paget's tissue.

Methods.

Vulvar Paget's cases from 1992 to 2007 from two institutions were identified by pathology database search. Regulatory T-cells were identified with FOXP3 immunohistochemistry and quantified at the dermal-epidermal junction using image analysis software. Thirteen non-neoplastic inflammatory cases were stained for comparison.

Results.

Cases included 33 women treated for primary vulvar Paget's, and 7 referred at recurrence. Of the 24 primary cases with greater than 5 months follow-up, recurrence was documented in 12/24(50%). Eight women (20%) recurred multiple times, but no recurrences were invasive. Significantly more patients with positive margins developed recurrent disease (82% vs 23%, p = 0.01). Secondary neoplasms occurred in 10/40(25%). FOXP3+ cells at the dermal-epidermal junction were quantified in 29 primary and 13 recurrent tissue samples. FOXP3+ cells were absent in surrounding normal vulvar skin. FOXP3+ cells averaged 66/HPF in primary vulvar Paget's and 66/HPF in recurrent Paget's, compared to 22/HPF in non-neoplastic inflammatory cases (p = 0.0003, p = 0.001). Primary cases with positive surgical margins had more FOXP3+ cells than those with negative margins (85 vs 49, p = 0.01). Recurrent cases with positive margins had more FOXP3+ cells than negative cases (84 vs 33, p = 0.06). FOXP3 levels in primary specimens were higher in cases which recurred (78 vs 35, p = 0.02).

Conclusions.

Increased regulatory T-cells may be associated with more extensive cases of vulvar Paget's disease that result in positive surgical margins and are associated with recurrence of disease, suggesting immunosuppression as a key factor.