Maaike H.M. Oonk

Sentinel Node Dissection Is Safe in the Treatment of Early-Stage Vulvar Cancer

PURPOSE To investigate the safety and clinical utility of the sentinel node procedure in early-stage vulvar cancer patients. PATIENTS AND METHODS A multicenter observational study on sentinel node detection using radioactive tracer and blue dye was performed in patients with T1/2 (< 4 cm) squamous cell cancer of the vulva. When the sentinel node was found to be negative at pathologic ultrastaging, inguinofemoral lymphadenectomy was omitted, and the patient was observed with follow-up for 2 years at intervals of every 2 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From March 2000 until June 2006, a sentinel node procedure was performed in 623 groins of 403 assessable patients. In 259 patients with unifocal vulvar disease and a negative sentinel node (median follow-up time, 35 months), six groin recurrences were diagnosed (2.3%; 95% CI, 0.6% to 5%), and 3-year survival rate was 97% (95% CI, 91% to 99%). Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy (wound breakdown in groin: 11.7% v 34.0%, respectively; P < .0001; and cellulitis: 4.5% v 21.3%, respectively; P < .0001). Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy (recurrent erysipelas: 0.4% v 16.2%, respectively; P < .0001; and lymphedema of the legs: 1.9% v 25.2%, respectively; P < .0001). CONCLUSION In early-stage vulvar cancer patients with a negative sentinel node, the groin recurrence rate is low, survival is excellent, and treatment-related morbidity is minimal. We suggest that sentinel node dissection, performed by a quality-controlled multidisciplinary team, should be part of the standard treatment in selected patients with early-stage vulvar cancer.

Size of sentinel-node metastasis and chances of non-sentinel-node involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study

BACKGROUND Currently, all patients with vulvar cancer with a positive sentinel node undergo inguinofemoral lymphadenectomy, irrespective of the size of sentinel-node metastases. Our study aimed to assess the association between size of sentinel-node metastasis and risk of metastases in non-sentinel nodes, and risk of disease-specific survival in early stage vulvar cancer. METHODS In the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V), sentinel-node detection was done in patients with T1-T2 (<4 cm) squamous-cell vulvar cancer, followed by inguinofemoral lymphadenectomy if metastatic disease was identified in the sentinel node, either by routine examination or pathological ultrastaging. For the present study, sentinel nodes were independently reviewed by two pathologists. FINDINGS Metastatic disease was identified in one or more sentinel nodes in 135 (33%) of 403 patients, and 115 (85%) of these patients had inguinofemoral lymphadenectomy. The risk of non-sentinel-node metastases was higher when the sentinel node was found to be positive with routine pathology than with ultrastaging (23 of 85 groins vs three of 56 groins, p=0.001). For this study, 723 sentinel nodes in 260 patients (2.8 sentinel nodes per patient) were reviewed. The proportion of patients with non-sentinel-node metastases increased with size of sentinel-node metastasis: one of 24 patients with individual tumour cells had a non-sentinel-node metastasis; two of 19 with metastases 2 mm or smaller; two of 15 with metastases larger than 2 mm to 5 mm; and ten of 21 with metastases larger than 5 mm. Disease-specific survival for patients with sentinel-node metastases larger than 2 mm was lower than for those with sentinel-node metastases 2 mm or smaller (69.5%vs 94.4%, p=0.001). INTERPRETATION Our data show that the risk of non-sentinel-node metastases increases with size of sentinel-node metastasis. No size cutoff seems to exist below which chances of non-sentinel-node metastases are close to zero. Therefore, all patients with sentinel-node metastases should have additional groin treatment. The prognosis for patients with sentinel-node metastasis larger than 2 mm is poor, and novel treatment regimens should be explored for these patients.

A comparison of quality of life between vulvar cancer patients after sentinel lymph node procedure only and inguinofemoral lymphadenectomy

OBJECTIVES The SLN-procedure has been introduced in vulvar cancer treatment to reduce morbidity and thereby improve quality of life. Aim of this study was to compare quality of life in vulvar cancer patients who were treated with a SLN-procedure only to those who underwent inguinofemoral lymphadenectomy. Moreover, it was evaluated what patients would advise relatives on the application of the SLN-procedure in light of possible false negative results. METHODS Patients who participated in the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) were invited to fill out three questionnaires: the EORTC QLQ-C30, a vulvar specific questionnaire and a questionnaire about the opinion of patients on new treatment options. Patients who only underwent SLN-procedure were compared to those who subsequently underwent inguinofemoral lymphadenectomy because of a positive SLN. RESULTS With a response rate of 85%, 35 patients after the SLN-procedure and 27 patients after inguinofemoral lymphadenectomy filled out the questionnaires. No difference in overall quality of life was observed between the two groups. The major difference was the increase in complaints of lymphedema of the legs after inguinofemoral lymphadenectomy. The majority of patients would advise the SLN-procedure to relatives. Patients after inguinofemoral lymphadenectomy were more reserved concerning the acceptable false negative rate of a new diagnostic procedure. CONCLUSIONS Patients who underwent the SLN-procedure report less treatment related morbidity compared to those who underwent inguinofemoral lymphadenectomy. However, this did not influence overall quality of life. Furthermore, patients who underwent inguinofemoral lymphadenectomy are more reserved in advising the SLN-procedure to relatives.

Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I

OBJECTIVE In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. METHODS From 2000 until 2006 GROINSS-V-I included 377 patients with unifocal squamous cell carcinoma of the vulva (T1, <4 cm), who underwent the SN-procedure. Only in case of SN metastases an inguinofemoral lymphadenectomy was performed. For the present study follow-up was completed until March 2015. RESULTS Themedian follow-up was 105 months (range 0–179). The overall local recurrence ratewas 27.2% at 5 years and 39.5% at 10 years after primary treatment, while for SN-negative patients 24.6% and 36.4%, and for SN-positive patients 33.2% and 46.4% respectively (p = 0.03). In 39/253 SN-negative patients (15.4%) an inguinofemoral lymphadenectomy was performed, because of a local recurrence. Isolated groin recurrence rate was 2.5% for SN-negative patients and 8.0% for SN-positive patients at 5 years. Disease-specific 10-year survival was 91% for SN-negative patients compared to 65% for SN-positive patients (p b .0001). For all patients, 10-year disease-specific survival decreased from 90% for patients without to 69% for patients with a local recurrence (p b .0001).

Sentinel lymph node biopsy in the management of gynecologic cancer.

Purpose of review To summarize current knowledge and recent advances in sentinel lymph node (SLN) concept in the three most frequent gynecological cancers. Recent findings In cervical cancer, SLN biopsy and ultrastaging has high sensitivity in lymph node staging in patients with bilaterally detected SLN. The presence of micrometastasis is associated with shortened survival. In endometrial cancer, SLN biopsy incorporating an institutional mapping algorithm and ultrastaging has been shown to significantly reduce false-negative rates and increase sensitivity and negative predictive value. Summary SLN biopsy and ultrastaging is useful in current management of patients with early-stage cervical cancer for multiple reasons, such as the reliable detection of key lymph nodes, identification of micrometastasis and intraoperative triage of patients. Although a complete or selective pelvic and paraaortic lymphadenectomy for adequate staging remains the standard treatment approach in patients with early-stage endometrial cancer, SLN biopsy has been shown to be safe and effective in detecting lymph node metastases. The application of the SLN procedure is safe in patients with early-stage unifocal squamous cell cancer of the vulva (<4 cm) and no suspicious enlarged lymph nodes at imaging.

Modern management of vulvar cancer.

Purpose of review The radical surgical approach in the treatment of vulvar cancer patients has led to a favourable prognosis for the majority of patients with early stage vulvar cancer. However, morbidity is impressive, leading to more individualized treatment. The authors have reviewed the most recent literature on the pros and cons of the modifications in treatment, including surgery and primary radiotherapy, for primary squamous cell carcinoma of the vulva and vulvar melanoma. Recent findings The sentinel lymph node procedure is a promising method of staging in patients with early stage squamous cell carcinoma of the vulva and possibly for patients with vulvar melanoma, but its safety still has to be proved. Less radical surgery has led to a higher local and regional recurrence rate. There may be a role for primary radiotherapy of the groin in a selected group of patients. Summary The authors have concluded that the individualization of treatment for vulvar cancer patients has led to a decrease in morbidity but an increase in recurrences. The increase in recurrences does not appear to compromise prognosis, probably because of the lack of power, based on the low incidence of vulvar cancer. The sentinel lymph node procedure and primary radiotherapy are promising methods to reduce the morbidity of treatment but their safety needs to be studied in randomized trials.

Adjuvant radiotherapy in patients with vulvar cancer and one intra capsular lymph node metastasis is not beneficial

AIM OF THE STUDY The aim of the study was to analyze the benefit from adjuvant radiotherapy in patients with vulvar cancer and a single positive node without extra capsular spread. MATERIALS AND METHODS The study population comprised data of 75 patients with vulvar cancer and one lymph node metastasis. The patients were treated in three different university centers in Amsterdam, Groningen and Rotterdam between 1984 and 2005. RESULTS Out of 75 patients, 31 (41%) were treated with adjuvant radiotherapy. Both disease-free survival (DFS) and disease-specific survival (DSS) were comparable between the groups who did and who did not receive adjuvant radiotherapy (HR 0.98, 95% CI 0.45-2.14, p=0.97 and HR=1.02, 95% CI 0.42-2.47, p=0.96). CONCLUSION We could not demonstrate any beneficial effect of adjuvant radiotherapy in the group of patients with one intra capsular metastasis.

Current controversies in the management of patients with early-stage vulvar cancer.

Purpose of review The purpose of this review is to outline current controversies in management of early-stage vulvar cancer. The main focus will be on the procedures for assessing the sentinel node and the treatment of those with evidence of metastatic involvement. Recent findings Assessment of the sentinel node has recently been introduced into the standard treatment of early-stage squamous cell vulvar cancer. The combination of a radioactive tracer and blue dye is the most accurate technique for sentinel node detection. Preoperative imaging is recommended to rule out gross nodal involvement and ultrasound with fine needle aspiration cytology by an experienced radiologist appears to have the highest sensitivity/specificity for detecting metastases, although large comparative studies are not available. All patients with sentinel node metastases require additional treatment to the groin, independent of the size of metastasis in the sentinel node and currently this involves inguinofemoral lymphadenectomy. Further research is ongoing to investigate the role of radiotherapy instead of lymphadenectomy. The little experience there is of sentinel node biopsy in vulvar melanoma suggests that the procedure is feasible and inclusion criteria should follow those of cutaneous melanoma. Summary Sentinel node biopsy is safe in treatment of early-stage vulvar cancer. Ongoing studies are investigating the optimal additional treatment for patients with a positive sentinel node in terms of efficacy and morbidity.

Treatment regimen, surgical outcome and T cell differentiation influence prognostic benefit of tumor-infiltrating lymphocytes in high grade serous ovarian cancer

Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with a better prognosis in high-grade serous ovarian cancer (HGSC). However, it is largely unknown how this prognostic benefit of TIL relates to current standard treatment of surgical resection and (neo-)adjuvant chemotherapy. To address this outstanding issue, we compared TIL infiltration in a unique cohort of patients with advanced-stage HGSC primarily treated with either surgery or neoadjuvant chemotherapy. Experimental Design: Tissue microarray slides containing samples of 171 patients were analyzed for CD8+ TIL by IHC. Freshly isolated CD8+ TIL subsets were characterized by flow cytometry based on differentiation, activation, and exhaustion markers. Relevant T-cell subsets (CD27+) were validated using IHC and immunofluorescence. Results: A prognostic benefit for patients with high intratumoral CD8+ TIL was observed if primary surgery had resulted in a complete cytoreduction (no residual tissue). By contrast, optimal (<1 cm of residual tumor) or incomplete cytoreduction fully abrogated the prognostic effect of CD8+ TIL. Subsequent analysis of primary TIL by flow cytometry and immunofluorescence identified CD27 as a key marker for a less-differentiated, yet antigen-experienced and potentially tumor-reactive CD8+ TIL subset. In line with this, CD27+ TIL were associated with an improved prognosis even in incompletely cytoreduced patients. Neither CD8+ nor CD27+ cell infiltration was of prognostic benefit in patients treated with neoadjuvant chemotherapy. Conclusions: Our findings indicate that treatment regimen, surgical result, and the differentiation of TIL should all be taken into account when studying immune factors in HGSC or, by extension, selecting patients for immunotherapy trials. Clin Cancer Res; 22(3); 714–24. ©2015 AACR.

Update on the sentinel lymph node procedure in vulvar cancer

Currently, standard treatment for early-stage vulvar cancer typically includes wide local excision of the primary tumor and inguinofemoral lymphadenectomy. The morbidity of this treatment is high. The sentinel lymph node (SLN) procedure provides us with a technique for determining the status of the regional lymph nodes with less treatment-related morbidity. Recently, a large multicenter observational study provided level 3 evidence indicating that it appears safe to omit inguinofemoral lymphadenectomy in case of a negative SLN. This review focuses on the different aspects of the SLN procedure in vulvar cancer.