Potential histological discordance revealed by second review in the national rare gynecological cancer network (TMRG).

INTRODUCTION: Since 2010, the network of rare malignant tumors of the ovary (TMRG) was developed to optimize the management of patients, also allowing a histological second opinion of rare ovarian tumors. The aim of this work was to study the contribution of second opinion to improve histological diagnostic accuracy on ovarian rare malignant tumors included in the TMRG database. MATERIAL AND METHODS: Histological data of patients diagnosed with a rare ovarian tumor included in TMRG network over a one-year period (2018) were collected. Initial diagnoses were compared with second opinion from national gynecological pathologist experts. The modalities of histological second opinion requests were studied, as well as the histological characteristics of the tumors. The discordances were classified as minor (if the modification of histological diagnosis did not change patient management) and major (if the patient management can be modified). RESULTS: Of 1185 included patients, 937 matched the inclusion criteria. Full concordance between primary diagnosis and expert second opinion was reached in 611 cases (65,3%), minor discordance was seen in 114 (12,2%) and major discordance in 209 (22,3%) of cases. In systematic review requested by the network, 26% (n = 137) of cases were reported with a change in histological diagnosis, while the change concerned 44% (n = 186) of cases for a second opinion spontaneously requested by the initial pathologist. The discrepancies concerned all categories of ovarian tumors, with a majority of mucinous tumors (43% of major discordances), followed by stromal and sex-cord tumors (13.8% of major discordances) and clear cell tumors (12,4% of major discordances). CONCLUSION: This analysis confirms the diagnostic difficulty of ovarian tumors, due to their rarity and morphological heterogeneity. French pathologists are aware of these difficulties and spontaneously refer ovarian tumors with unusual histology for a second opinion and collaborate with rare tumor networks for systematic review.

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.

[Biopathology of ovarian carcinomas early and advanced-stages: Article drafted from the French guidelines in oncology entitled "Initial management of patients with epithelial ovarian cancer" developed by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY under the aegis of CNGOF and endorsed by INCa]. / Biopathologie des carcinomes ovariens des stades précoces et avancés. Article rédigé sur la base de la recommandation nationale de bonnes pratiques cliniques en cancérologie intitulée « Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire ¼ élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY sous l'égide du CNGOF et labellisée par l'INCa.

OBJECTIVES: Ovarian carcinomas represent a heterogeneous group of lesions with specific therapeutic management for each histological subtype. Thus, the correct histological diagnosis is mandatory. MATERIAL AND METHODS: References were searched by PubMed from January 2000 to January 2018 and original articles in French and English literature were selected. RESULTS AND CONCLUSIONS: In case of ovarian mass suspicious for cancer, a frozen section analysis may be proposed, if it could impact the surgical management. A positive histological diagnosis of ovarian carcinoma (type and grade) has to be rendered on histological (and not cytological) material before any chemotherapy with multiples and large sized biopsies. In case of needle biopsy, at least three fragments with needles>16G are needed. Histological biopsies need to be formalin-fixed (4% formaldehyde) less than 1h after resection and at least 6hours fixation is mandatory for small size biopsies. Tissue transfer to pathological labs up to 48hours under vacuum and at +4°C (in case of large surgical specimens) may be an alternative. Gross examination should include the description of all specimens and their integrity, the site of the tumor and the dimension of all specimens and nodules. Multiples sampling is needed, including the capsule, the solid areas, at least 1 to 2 blocks per cm of tumor for mucinous lesions, the Fallopian tube in toto, at least 3 blocks on grossly normal omentum and one block on the largest omental nodule. WHO classification should be used to classify the carcinoma (type and grade), with the use of a panel of immunohistochemical markers. High-grade ovarian carcinomas (serous and endometrioid) should be tested for BRCA mutation and in case of a detectable tumor mutation, the patient should be referred to an oncogenetic consultation.

Shear wave elastography of tumour growth in a human breast cancer model with pathological correlation.

OBJECTIVE: To assess stiffness in a human breast cancer implanted in mice using shear wave elastography (SWE) during tumour growth and to correlate the results with pathology. METHODS: Local ethics committee for animal research approval was obtained. A human invasive ductal carcinoma was implanted subcutaneously in 24 athymic nude female mice. Ultrasound was longitudinally performed in 22 tumours, every 1-2 weeks. Maximum diameter and mean stiffness were collected. Seven tumours were measured both in vivo and ex vivo. Tumours of different sizes were removed for pathological analysis on which the percentages of viable cellular tissue, fibrosis and necrosis were measured. RESULTS: A total of 63 SWE measurements were performed. Stiffness increased during tumour growth with an excellent correlation with size (r = 0.94, P < 0.0001). No differences were found between the values of stiffness in vivo and ex vivo (P = 0.81). There was a significant correlation between elasticity and fibrosis (r = 0.83, P < 0.0001), a negative correlation with necrosis (r = -0.76, p = 0.0004) but no significant correlation with cellular tissue (r = 0.40, p = 0.1). CONCLUSION: Fibrosis plays an important role in stiffness as measured by SWE, whereas necrosis is correlated with softness. KEY POINTS: • In a breast cancer model, ultrasound tumour stiffness is correlated with size. • Stiffness changes with tumour growth are correlated with pathological changes. • Stiffness is very well correlated with proportion of tumour fibrosis. • Stiffness is inversely correlated with proportion of tumour necrosis. • Tumour stiffness measurements are similar in vivo and ex vivo.

Usefulness of routine intraoperative staging of suspicious adnexal tumours: illustration by two cases of adult granulosa cell tumour.

Granulosa cell tumours (GCTs) account for less than 3% of all ovarian malignancies but are among the most common sex cord-stromal tumours. They may develop at any age. Symptoms related to oestrogen production by the tumour may occur. Because GCTs are uncommon and cannot be diagnosed preoperatively, their management is challenging. Surgery with salpingo-oophorectomy and painstaking staging is mandatory. Adjuvant chemotherapy is required in some patients. We report two cases of adult GCTs that illustrate the usefulness of extensive abdominal exploration in every patient with a suspicious ovarian mass, to obviate the need for a second staging procedure. With this strategy, the prognosis is excellent, although the possibility of late recurrences requires prolonged follow-up.

[Update on malignant nonepithelial ovarian tumours]. / Tumeurs non épithéliales malignes de l'ovaire.

Malignant nonepithelial ovarian tumours represent less than 20% of ovarian cancers in adults. Apart from haematological tumours, there are mainly germ cell tumours and sex cordstromal ovarian tumours. These tumours affect young women and are diagnosed in early stages associated with a good prognosis. The management of malignant nonepithelial ovarian tumours is difficult because they are rare and because we have to propose an appropriate oncological treatment, preserving fertility for these women of child-bearing age. We propose an update on recent data in the literature, focusing on management.

Sentinel lymph nodes in endometrial cancer: is hysteroscopic injection valid?

We aimed to describe hysteroscopic peritumoral tracer injection for detecting sentinel lymph nodes (SLNs) in patients with endometrial cancer and to evaluate tolerance of the procedure, detection rate and location of SLNs. Five patients with early endometrial cancer underwent hysteroscopic radiotracer injection followed by lymphoscintigraphy, then by surgery with hysteroscopic peritumoral blue dye injection, and radioactivity measurement using an endoscopic handheld gamma probe. SLNs and other nodes were sent separately to the pathology laboratory. SLNs were evaluated by hematoxylin-eosin-saffron staining and, when negative, by immunohistochemistry. Tolerance of the injection by the patients was poor (mean visual analog scale score, 8/10). SLNs were detected in only two patients (external iliac and common iliac+paraaortic, respectively). Detection rates were 1/5 by radiotracer, 1/5 by dye, and 2/5 by the combined method. One SLN was involved in a patient whose other nodes were negative. In three patients no SLNs were found by radiotracer or blue dye. Of the 83 non sentinel nodes removed from these patients, none was involved. Hysteroscopic peritumoral injection may be more difficult than cervical injection and, in our experience, carries a lower SLN detection rate.

Performance of office hysteroscopy and endometrial biopsy for detecting endometrial disease in women at risk of human non-polyposis colon cancer: a prospective study.

The objective of this study was to report the value of diagnostic hysteroscopy and endometrial biopsy for the detection of complex atypical hyperplasia or cancer in asymptomatic human non-polyposis colon cancer (HNPCC) patients. The secondary objective was to evaluate the accuracy of hysteroscopy, using endometrial biopsy as a gold standard. Consecutive patients at risk of HNPCC evaluated between January 1, 1999, and June 30, 2006 were included if they underwent diagnostic hysteroscopy at least once. Patients with a history of hysterectomy and those unwilling to undergo diagnostic hysteroscopy were not included. Yearly follow-up evaluations included diagnostic hysteroscopy, with endometrial biopsy. Hysteroscopic and histologic findings were recorded and compared. We included 62 patients, of whom 13 had mismatch repair gene mutations and 49 met Amsterdam II criteria. Of 125 attempted hysteroscopies, 11 (8%) failed. Hysteroscopy showed normally appearing mucosa in 46 cases, nonmalignant lesions in 65 cases, and possibly malignant lesions in 3 cases with abnormal uterine bleeding. Endometrial biopsy was attempted in 116 cases and failed in 12 (10%). Three cases each of simple hyperplasia and of cancer were diagnosed. No preinvasive or invasive lesions were found in asymptomatic women. When compared to endometrial biopsy, sensitivity of hysteroscopy was 100% for the detection of hyperplasia or cancer. No cases of cancer were diagnosed in asymptomatic patients in our study. However, diagnostic hysteroscopy ensured the diagnosis of endometrial adenocarcinoma in HNPCC women with bleeding. Nevertheless, usefulness and optimal modalities of screening remain to be determined.

Sentinel node biopsy helps to diagnose spread of endometrial cancer. A case report.

BACKGROUND: The sentinel lymph node (SLN) could improve the staging of endometrial cancer. CASE: In a patient with endometrial cancer, preoperative lymphoscintigraphy showed a highly radioactive SLN in the left external iliac chain and a radioactive SLN in the right external iliac chain and at the promontory. Intraoperative lymphatic mapping using blue dye and a hand-held gamma probe showed the same nodes, as well as a blue node near the vena cava. Selective removal of these nodes allowed detection of a micrometastasis in the left external iliac node. Pelvic node dissection was performed, and a micrometastasis was found in a left non sentinel iliac node. CONCLUSION: The presence in our patient of micrometastases in a SLN and in a non-SLN belonging to the same chain confirms the value of SLN detection for diagnosing tumor spread.

Performance of laparoscopy in identifying malignant ovarian cysts.

BACKGROUND: Peroperative identification of malignancy is crucial to management planning for ovarian cysts. The aim of this study was to evaluate the performance of laparoscopy in identifying malignant ovarian cysts. METHODS: Patients undergoing laparoscopy for ovarian cysts from 1998 to 2001 were enrolled prospectively. Physical findings, Doppler ultrasonography, and serum CA 125 served to compute two risk-of-malignancy indexes (RMI-1 and RMI-2), and laparoscopy findings served to categorize lesions as benign, possibly malignant, or malignant. Frozen sections were examined as needed. Final histology was the reference. RESULTS: Of 313 patients, 294 had benign cysts, six borderline lesions, and 13 malignancies. Sensitivity and specificity were respectively 84 and 93% for RMI-1, 92 and 80% for RMI-2, 100 and 99% for laparoscopy, 91 and 100% for frozen sections, and 100 and 100% for laparoscopy plus frozen sections, which had 100% negative predictive value. Six (1.8%) adverse events occurred. CONCLUSIONS: Laparoscopy reliably identifies ovarian cancer and borderline disease. Morbidity is low compared to oncologic surgery.

p15(INK4b) in bladder carcinomas: decreased expression in superficial tumours.

The p15 gene which encodes a cyclin-dependent kinase inhibitor, is located in the 9p21 chromosomal region that is frequently deleted in human bladder transitional cell carcinomas (TCCs). The aim of the present paper is to study the potential involvement of the p15 gene in the evolution of TCCs. p15 mRNA expression was investigated by semi-quantitative RT-PCR in a series of 75 TCCs, 13 bladder cell lines and 6 normal bladder urothelia by semi-quantitative RT-PCR. p15 was expressed in the normal urothelium but p15 mRNA levels were significantly decreased in 66% of the superficial (Ta-T1) TCCs (P = 0.0015). In contrast, in muscle-invasive (T2-T4) TCCs, p15 expression differed widely between samples. p16 mRNA levels were also studied and there was no correlation between p15 and p16 mRNA levels, thus indicating that the two genes were regulated independently. Lower p15 expression in superficial tumours did not reflect a switch from quiescence to proliferative activity as normal proliferative urothelial controls did not present decreased p15 mRNA levels relative to quiescent normal urothelia. We further investigated the mechanisms underlying p15 down regulation. Homozygous deletions of the p15 gene, also involving the contiguous p16 gene, were observed in 42% of the TCCs with decreased p15 expression. No hypermethylation at multiple methylation-sensitive restriction sites in the 5;-CpG island of p15 was encountered in the remaining tumours. Our data suggest that decreased expression of p15 may be an important step in early neoplastic transformation of the urothelium and that a mechanism other than homozygous deletions or hypermethylation, may be involved in p15 down regulation.

Donor or recipient origin of post-transplantation lymphoproliferative disorders: evaluation by in situ hybridization.

Post-transplantation lymphoproliferative disorders (PTLDs) have been reported after bone marrow and solid-organ transplantation. It might be of interest to know the origin of PTLDs, because it has been suggested that a donor origin could be related to a better prognosis. We studied five cases of PTLD in sex-mismatched allografted recipients by in situ hybridization technique for chromosome Y on isolated cells as well as on frozen and on routinely fixed and paraffin-embedded material. Two proved to be of donor origin, including the only case of PTLD arising in the graft, and three of recipient origin. The best results were obtained on isolated cells, but it must be emphasized that hybridization on tissue sections from frozen material or from material fixed in formalin or in formalin-acetic acid-alcohol and then paraffin embedded also gave good results. Hybridization after fixation in Bouin's liquid was not reliable. These results suggest that evaluation of the origin of PTLDs can easily be performed on routinely processed cytologic and histologic material.