Should We Abandon Systematic Pelvic and Paraaortic Lymphadenectomy in Low-Grade Serous Ovarian Cancer?

BACKGROUND: Low-grade serous ovarian carcinoma (LGSOC) is a rare disease that accounts for 5% of all ovarian cancers and requires surgical complete debulking. To date, the prognostic value of pelvic and paraaortic lymphadenectomy remains unclear in this population. PATIENTS AND METHODS: This retrospective cohort of patients with a diagnosis of LGSOC was registered in the Tumeurs Malignes Rares Gynécologiques national network, between January 2000 and July 2017, at 25 centers. All LGSOC were confirmed after pathological review and operated by primary debulking surgery (PDS) or interval debulking surgery after neoadjuvant chemotherapy (NACT-IDS). Primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 126 patients were included, 86.1% were stage III/IV, and 74.6% underwent lymph node dissection (LND). According to the Completeness of Cancer Resection (CCR) score, 83.7% had complete resection. Median OS was 130 months, and median PFS was 41 months. Pelvic and paraaortic LND had no significant impact on OS (p = 0.78) or DFS (p = 0.93), and this was confirmed in subgroups (advanced stages FIGO III/IV, CCR score 0/1 or 2/3, and timing of surgery PDS or NACT-IDS). Histological positive paraaortic lymph nodes had a significant negative impact on PFS in the whole population (HR 2.21, 1.18-4.39, p = 0.02) and in the CC0/CC1 population (HR, 2.28, 1.13-4.59, p = 0.02). CONCLUSIONS: Systematic pelvic and paraaortic LND in patients with LGSOC improved neither overall nor PFS. A prospective trial would be necessary to validate these results but would be difficult to conduct due to the rarity of this disease.

Diagnostic value of frozen section examination of sentinel lymph nodes in early-stage cervical cancer at the time of ultrastaging.

OBJECTIVES: We aimed to assess the diagnostic value of frozen-section pathologic examination (FSE) of sentinel lymph nodes (SLN) in patients with early-stage cervical cancer. METHODS: Two French prospective multicentric database on SLN biopsy for cervical cancer (SENTICOL I and II) were analysed. Patients with IA to IIA1 2018 FIGO stage, who underwent SLN biopsy with both FSE and ultrastaging examination were included. RESULTS AND DISCUSSION: Between 2005 and 2012, 313 patients from 25 centers fulfilled the inclusion criteria. Metastatic involvement of SLN was diagnosed in 52 patients (16.6%). Macrometastases, micrometastases and isolated tumor cells (ITCs) were found in 27, 12 and 13 patients respectively. Among the 928 SLNs analysed, FSE identified 23 SLNs with macrometastases in 20 patients and 5 SLNs with micrometastases in 2 patients whereas no ITCs were identified. Ultrastaging of negative SLNs by FSE found macrometastases, micrometastases and ITCs in additional 7, 11 and 17 SLNs. Ultrastaging increased significantly the rate of patients with positive SLN from 7% to 16.6% (p < 0.0001). The sensitivity and the negative predictive value of FSE were 42.3% and 89.7% respectively or 56.4% and 94.1% if ITCs were excluded. False-negative cases were more frequent with tumor size ≥ 20 mm (OR = 4.46, 95%IC = [1.45-13.66], p = 0.01) and preoperative brachytherapy (OR = 4.47, 95%IC = [1.37-14.63], p = 0.01) and less frequent with patients included in higher volume center (>5 patients/year) (OR = 0.09, 95%IC = [0.02-0.51], p = 0.01). CONCLUSIONS: FSE of SLN had a low sensitivity for detecting micrometastases and ITCs and a high negative predictive value for SLN status. Clinical impact of false-negative cases has to be assessed by further studies.

Risk factors for failure of bilateral sentinel lymph node mapping in early-stage cervical cancer.

BACKGROUND: The objective of this study was to determine clinical, tumoral and surgical factors associated with successful bilateral sentinel lymph node mapping (SBM) in early-stage cervical cancer. METHODS: We performed an ancillary work on the data of two prospective trials on SLN biopsy for FIGO IA-IIA cervical cancer (SENTICOL I & II). Patients having Sentinel lymph node (SLN) mapping for early-stage cervical cancer were included between 2005 and 2012 from 28 French oncologic centers. SLN was detected by a combined labeling technique (blue and isotopic). RESULTS: 405 patients were included for analysis: SLNs were identified on at least one side of the pelvis in 381 patients (94.1%) and bilaterally in 326 patients (80.5%). The mean age was 45.4 years [22-85 years]. Most patients had IB1 pathologic FIGO 2018 stage (81.3%) and squamous cell carcinoma (71%). Surgeries were mainly performed by minimally invasive approach (368 patients - 90.9%). By multivariate analysis, lower SBM rate was significantly associated with Age ≥70 years (ORa = 0.02, 95%CI = [0.001-0.28], p = 0.004), tumor size larger than 20 mm (ORa = 0.46,95%CI = [0.21-0.99], p = 0.048) and Body-mass index higher than 30 kg/m2 (ORa = 0.28, 95%CI = [0.12-0.65], p = 0.003). SBM rate was significantly higher in high skills centers (>5patients/year) (ORa = 8.05, 95%CI = [2.06-31.50], p = 0.003) and in SENTICOL II (2009-2012) compared to SENTICOL I (2005-2007) (ORa = 2.6, 95%CI = [1.23-5.51], p = 0.01). CONCLUSIONS: In early-stage cervical cancer, bilateral SLN detection rates is lower in patients aged more than 70years, patients with BMI≥30 kg/m2 and larger tumor ≥20 mm whereas stronger experience of SLN biopsy technique improves bilateral SLN detection.

The French national network dedicated to rare gynecological cancers diagnosis and management could improve the quality of surgery in daily practice of granulosa cell tumors. A TMRG and GINECO group Study.

OBJECTIVE: The French national rare gynecological tumor network has been established to improve the quality of care through offering expertise in double reading histological diagnosis, reviewing cases and guiding management of these tumors through specialized multidisciplinary tumor boards and online clinical guidelines (www.ovaire-rare.com). The aim of this study is to evaluate the impact of the development and implementation of this network by assessing the conformity of medical practice with the guidelines concerning the granulosa cell tumors (GCTs). METHODS: This is a French nationwide study, including 463 patients (out of the 639 identified patients) with a definitive diagnosis of GCT between 2011 and 2016. Surgical practices were analyzed for conformity with the current guidelines (www.ovaire-rare.org). Medical records, surgical and pathological reports were systematically analyzed. Total conformity was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysterectomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsies and peritoneal cytology) according to the FIGO stage. Partial conformity referred to a conservative or radical surgery without surgical staging and non-conformity was defined as a non-optimal surgery as recommended by the guidelines. RESULTS: Median age at diagnosis was 49 years old (range 10-89). The median size of tumor was 94 mm (range 5-400). Radical surgery was performed in 240 patients (52%); while a fertility-sparing surgery was performed in 98 cases (21%). A surgical staging was performed in 76 cases (16%) and an evaluation of the endometrium in 289 cases (62%). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (30%) and not assessable in 48 cases (10%). A statistically significant difference for compliance was observed in restaging surgery (p < 0,001), radical surgery (p = 0,017) and the period (before or after) of the implementation of the network (p < 0,001). Survival analyses did not allow us to demonstrate a significant difference in overall survival nor in PFS although there was a trend in favor of optimal surgery compared to incomplete/non optimal surgery. CONCLUSION: Surgical management's conformity to the guidelines increases over time from 2011 to 2016. According to this study, the implementation of a national network dedicated to rare gynecologic tumors seems to significantly improve the surgical management of the patients with ovarian granulosa cell tumors.

Predictive factors of unexpected lymphatic drainage pathways in early-stage cervical cancer.

OBJECTIVES: The purpose of this study was to describe sentinel lymph nodes (SLN) topography in patients with early-stage cervical cancer and to determine factors associated with atypical lymphatic drainage pathway (LDP). METHODS: We analyzed the data of two prospective multicentric trials on SLN biopsy for cervical cancer (SENTICOL I and II) in women undergoing surgery for early-stage cervical cancer. SLN detection was realized with a combined labeling technique (Patent blue and radioactive tracer). Patients having bilateral SLN detection were included. Univariate and Multivariate analysis were performed by patients and by side to assess clinical and pathologic factors that may predict atypical LDP. RESULTS: Between January 2005 and July 2012, 326 patients with 1104 intraoperative detected SLNs fulfilled the inclusion criteria. The SLNs were mainly located in the interiliac or external iliac area in 83.2%. The other localizations were: 9.2% in the common iliac area, 3.9% in the parametrium, 1.6% in the promontory area, 1.5% in the paraaortic area and 0.5% in other areas. Thirty-five patients (10.7%) had atypical SLN without SLN in typical area on one or both sides. In multivariate analysis, tumor size ≥20 mm appeared as an independent factor of having at least one exclusive atypical LDP (ORa = 3.95 95%CI = [1.60-9.78], p = 0.003). Multiparity decreased significantly the probability of having at least one exclusive atypical LDP (ORa = 0.16 95%CI = [0.07-0.39], p < 0.0001). CONCLUSIONS: Tumor size larger than 20 mm and nulliparity increase the risk of having exclusive atypical LDP in early-stage cervical cancer.

Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer.

BACKGROUND: The role of tumor-infiltrating lymphocytes (TILs) in breast cancer has been extensively studied over the last decade. High TILs levels have been associated with pathological response rate in the neoadjuvant setting and with better outcomes in the adjuvant setting. However, little attention has been paid to changes in TILs and residual TIL levels after neoadjuvant chemotherapy (NAC). We investigated TIL levels before, after chemotherapy, and their dynamics during treatment; and we assessed the correlation of these levels with response to NAC and prognosis. MATERIALS AND METHODS: We identified 175 patients with primary HER2-positive breast cancers receiving NAC+/- trastuzumab between 2002 and 2011. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Univariate and multivariate analyses were carried out to assess the association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival. RESULTS: Baseline TIL levels were not significantly associated with pCR. TIL levels decreased during treatment in 78% of the patients. The magnitude of the decrease was strongly associated with pCR. After chemotherapy, TIL levels were high in tumors displaying aggressive patterns (high residual cancer burden score, mitotic index >22, tumor cellularity >5%). In the population with residual disease, TIL levels >25% at the end of NAC were significantly associated with an adverse outcome (TILs >25%, HR = 7.98, P = 0.009) after multivariate analyses including BMI, post-NAC mitotic index and tumor grade. CONCLUSION: A decrease in TIL levels during chemotherapy was positively associated with response to treatment. In tumor failing to achieve pCR, post-NAC lymphocytic infiltration was associated with higher residual tumor burden and adverse clinical outcome. Further studies are required to characterize immune infiltration in residual disease to identify candidates who could benefit from second-line therapy trials including immune checkpoint inhibitors.

Predictive factors of severe perioperative morbidity of radical hysterectomy with lymphadenectomy in early-stage cervical cancer: A French prospective multicentric cohort of 248 patients.

OBJECTIVE: The purpose of this study was to assess the postoperative morbidity after radical hysterectomy (RH) for early-stage cervical cancer and to determine risk factors of severe perioperative morbidity. METHODS: Data of two prospective trials on sentinel node biopsy for cervical cancer (SENTICOL I & II) were analysed. Patients having a radical hysterectomy were included between 2005 and 2012 from 25 French oncologic centers. Postoperative complications were prospectively recorded in a pre-specified analysis. RESULTS: 248 patients met the inclusion criteria. The median age was 44.5 years [25-85]. 88.7% of patients had a stage IB1 disease. There were 71.4% epidermoid carcinomas and 25% adenocarcinomas. 125 patients (50.4%) had a laparoscopic-assisted vaginal RH, 88 patients (35.5%) had a total laparoscopic RH, 26 patients (10.5%) had an open RH and 9 patients (3.6%) had a robotic-assisted RH. Sixteen patients (6.4%) had intraoperative complications. On a multivariate analysis, intraoperative complications were significantly associated with BMI >30 kg/m2. The urinary, lymphovascular and neurologic complications rates were respectively 34.3%, 20.6% and 19.8%. 31 patients (12.5%) had severe postoperative complications (Clavien-Dindo ≥ 3 or CTCAE ≥ 3). On multivariate analysis, severe postoperative complications were associated with parametrial involvement, preoperative brachytherapy and inclusion in low surgical skills center. CONCLUSIONS: This study based on prospective data showed that RH has low severe postoperative complications. The main complications were urinary infections and lower limb lymphedema. Patients with early-stage cervical cancer should be referred to expert center to ensure best surgical outcomes.

Precaval positive sentinel lymph node with bilateral negative pelvic sentinel lymph node in low-risk endometrial cancer patient.

We here describe a case report of a positive precaval sentinel lymph node with negative pelvic sentinel lymph node in a patient with endometrial cancer. A 45-years-old woman was diagnosed with a grade 2 endometrioid carcinoma of the endometrium. She was treated with a hysterectomy and bilateral salpingo-oophorectomy, associated with dissection of sentinel lymph nodes (SLNs). We detected bilateral external and common bilateral iliac nodes and one precaval node. At pathological examination the pelvic nodes were non-metastatic, but the precaval node was positive. In this patient, sentinel node biopsy improved risk-assessment and adjuvant treatment.

What about sentinel lymph node biopsy for early breast cancer during pregnancy?

Pregnancy-associated breast cancer is rare, but this clinical situation arises in 1/10,000-1/3000 pregnancies. In patients presenting an early-stage breast tumor devoid of clinically pathological lymph node, sentinel lymph node (SLN) biopsy has not yet been validated as a routine procedure for pregnant women due to the lack of data in the literature. The blue dye injection is not recommended because of 2% theoretical risk of anaphylactic shock. Several studies have shown that Tc99m injection at conventional dose between 12.1 and 18.5MBq exposed the fetus to an irradiation between 0.011 and 0.0245mSv much below the 50mSv recommended threshold. As evidenced by lymphoscintigraphy scans, the dose of injected Tc99m is localized at the injection site and in the SLN. According to the literature, the SLN technique does not seem to impact the fetal or obstetrical prognosis. Studies involving larger cohorts are required to confirm these data and to indicate this technique in pregnant women. Considering the benefit for the patient and the low risk incurred on both fetal and obstetrical levels, it appears reasonable to discuss the indication of SLN on a case-by-case basis in multidisciplinary oncologic meetings.

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis.

Triple-negative breast cancer (TNBC) is a heterogeneous group of aggressive breast cancers for which no targeted treatment is available. Robust tools for TNBC classification are required, to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 3,247 primary human breast cancer samples from 21 publicly available datasets, using a five-step method: (1) selection of TNBC samples by bimodal filtering on ER-HER2 and PR, (2) normalization of the selected TNBC samples, (3) selection of the most variant genes, (4) identification of gene clusters and biological gene selection within gene clusters on the basis of String© database connections and gene-expression correlations, (5) summarization of each gene cluster in a metagene. We then assessed the ability of these metagenes to predict prognosis, on an external public dataset (METABRIC). Our analysis of gene expression (GE) in 557 TNBCs from 21 public datasets identified a six-metagene signature (167 genes) in which the metagenes were enriched in different gene ontologies. The gene clusters were named as follows: Immunity1, Immunity2, Proliferation/DNA damage, AR-like, Matrix/Invasion1 and Matrix2 clusters respectively. This signature was particularly robust for the identification of TNBC subtypes across many datasets (n = 1,125 samples), despite technology differences (Affymetrix© A, Plus2 and Illumina©). Weak Immunity two metagene expression was associated with a poor prognosis (disease-specific survival; HR = 2.68 [1.59-4.52], p = 0.0002). The six-metagene signature (167 genes) was validated over 1,125 TNBC samples. The Immunity two metagene had strong prognostic value. These findings open up interesting possibilities for the development of new therapeutic interventions.

p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer.

The transition of ductal carcinoma in situ (DCIS) to invasive breast carcinoma requires tumor cells to cross the basement membrane (BM). However, mechanisms underlying BM transmigration are poorly understood. Here, we report that expression of membrane-type 1 (MT1)-matrix metalloproteinase (MMP), a key component of the BM invasion program, increases during breast cancer progression at the in situ to invasive breast carcinoma transition. In the intraductal xenograft model, MT1-MMP is required for BM transmigration of MCF10DCIS.com breast adenocarcinoma cells and is overexpressed in cell clusters overlying focal BM disruptions and at the invasive tumor front. Mirrored upregulation of p63 and MT1-MMP is observed at the edge of MCF10DCIS.com xenograft tumors and p63 is required for induction of MT1-MMP-dependent invasive program in response to microenvironmental signals. Immunohistochemistry and analysis of public database reveal that p63 and MT1-MMP are upregulated in human basal-like breast tumors suggesting that p63/MT1-MMP axis contributes to progression of basal-like breast cancers with elevated p63 and MT1-MMP levels.