Pierre-Adrien Bolze

Formalised consensus of the European Organisation for Treatment of Trophoblastic Diseases on management of gestational trophoblastic diseases

Gestational trophoblastic disease (GTD) is a spectrum of cellular proliferations arising from trophoblast. Their invasive and metastatic potential sometimes requires chemotherapy and/or surgery. Current management is generally associated with favourable prognosis. Therefore, treatments must be chosen according to the desire for further childbearing of each patient. The European Organisation for Treatment of Trophoblastic Diseases (EOTTD) is dedicated to optimise diagnosis, treatment, follow-up and research in GTD by bringing together knowledge of clinicians and researchers from 29 countries working in the field of GTD in Europe. This study assessed the level of agreement among an expert panel of the EOTTD in order to rationalise the management of patients in Europe. The RAND/UCLA Appropriateness Method was used to combine the best available scientific evidence with the collective judgment of experts to yield a statement regarding the appropriateness of performing a procedure at the level of patient-specific symptoms, medical history and test results. There was an agreement for 54 statements while the experts showed a disagreement for two statements. As there is little evidence from randomised trials on which to base recommendations about management of GTD, many of these recommendations are based on expert opinion derived from changes in management fact that have improved outcomes from nearly 100% fatality to nearly 100% cure rates. However, a large agreement among experts is invaluable to the individual clinician who is struggling to decide whether a fertility-sparing treatment of hydatidiform mole or a low-risk GTN can be chosen and how it must be conducted.

Mortality rate of gestational trophoblastic neoplasia with a FIGO score of ≥13.

BACKGROUND Gestational trophoblastic diseases include premalignant (partial and complete hydatidiform moles) and malignant entities referred to as gestational trophoblastic neoplasia. Use of the International Federation of Gynecology and Obstetrics prognostic score is encouraged in cases of gestational trophoblastic neoplasia to predict the potential for the development of resistance to single-agent chemotherapy. An International Federation of Gynecology and Obstetrics score of ≥7 defines a high-risk patient and requires combination chemotherapy. Appropriate and rapid diagnosis, treatment by specialized centers, and reduction of early deaths at the time of chemotherapy initiation have led to significant improvements in survival for patients with high-risk gestational trophoblastic neoplasia. There is a crucial need for the early identification of high-risk patients with gestational trophoblastic neoplasia who have an increased death risk to organize their treatment in highly specialized centers. OBJECTIVES The purpose of this study was to describe cases of gestational trophoblastic neoplasia that have resulted in death, particularly in a subgroup with an International Federation of Gynecology and Obstetrics prognostic score of ≥13, for whom low-dose etoposide and cisplatin induction chemotherapy recently was shown to reduce early death rate. STUDY DESIGN We identified 974 patients from the French Center for Trophoblastic Diseases who had a diagnosis of gestational trophoblastic neoplasia from November 1999 to March 2014. Among 140 patients who were at high risk of resistance to single-agent chemotherapy (International Federation of Gynecology and Obstetrics score, ≥7), 29 patients (21%) had a score of ≥13. Mortality rate was estimated with the use of the Kaplan-Meier method. RESULTS The 5-year overall mortality rate, after the exclusion of placental site trophoblastic tumors and epithelioid trophoblastic tumors, was 2% for patients with gestational trophoblastic neoplasia (95% confidence interval, 1.25-3.13%). High-risk patients had a 5-year mortality rate of 12% (95% confidence interval, 7.49-18.9%). Patients with an International Federation of Gynecology and Obstetrics score of ≥13 had a higher 5-year mortality rate (38.4%; 95% confidence interval, 23.4-58.6%) and accounted for 52% of the deaths in the entire cohort. Early deaths, defined as those that occur within 4 weeks after treatment initiation, occurred in 8 patients of the entire cohort. Six of them had an International Federation of Gynecology and Obstetrics score of ≥13 at presentation, of whom 5 patients had brain and/or liver metastases. CONCLUSION Gestational trophoblastic diseases with an International Federation of Gynecology and Obstetrics score of ≥13 have an increased risk of early death. We suggest that an International Federation of Gynecology and Obstetrics score of ≥13 becomes a consensual criterion for prediction of patients with gestational trophoblastic neoplasia with increased risk of death, particularly early death. These patients justify treatment in highly specialized gestational trophoblastic disease centers and may benefit from the use of induction low-dose etoposide and cisplatin.

First confirmation by genotyping of transplacental choriocarcinoma transmission

A mother developed multimetastatic gestational choriocarcinoma 13 months after delivery, and her infant died aged 11 months from the same tumor. The transplacental choriocarcinoma transmission was confirmed by genotyping. Henceforth, we recommend a 2-year maternal human chorionic gonadotropin follow-up after neonatal choriocarcinoma and extensive imaging if the human chorionic gonadotropin rises.

PD-L1 Expression in Premalignant and Malignant Trophoblasts From Gestational Trophoblastic Diseases Is Ubiquitous and Independent of Clinical Outcomes.

Objective Recently reported expression of programmed cell death 1 ligand 1 (PD-L1) in gestational trophoblastic diseases (GTDs) suggests that the immune tolerance of pregnancy might be hijacked during neoplastic process. We assessed PD-L1 protein expression in premalignant and malignant GTD lesions and analyzed associations with disease severity and chemotherapy outcomes. Methods We included 83 GTD whole-tissue sections from 76 patients in different treatment settings. PD-L1 protein expression was assessed with immunohistochemistry in each trophoblast subtype with the Allred total score (ATS), which combines intensity and proportion expression on a 0- to 8-point scale. Peritumoral immune infiltrate was scored on hematoxylin-eosin-safran–stained slides. Results PD-L1 expression was ubiquitous and strong in all GTD trophoblast subtypes. For invasive moles, ATS scores were maximal at 8 in 100%, 100%, and 75% of syncytiotrophoblast, villous cytotrophoblast, and extravillous cytotrophoblast specimens, respectively. For choriocarcinomas, ATS was 8 in 80% of specimens. Immune infiltrates were moderate to severe in 61%, 100%, and 100% of peritumoral zones of choriocarcinoma, epithelioid trophoblastic tumor, and invasive moles, respectively. Because of the homogeneous pathological findings, no significant differences in PD-L1 expression profiles or peritumoral immune infiltrates were found regarding FIGO (International Federation of Gynecology Obstetrics) prognostic score, fatal outcome, or chemosensitivity. Conclusions We confirm that PD-L1 is constitutively expressed in all GTD premalignant and malignant trophoblast subtypes, independently from FIGO score, chemoresistance, or fatal outcomes, thereby suggesting a crucial role for PD-L1 in the development and tolerance of GTD. Assessment of anti–PD-L1 drug in GTD patients has been activated.

Place de l’hystérectomie d’emblée dans la prise en charge des tumeurs trophoblastiques gestationnelles à bas risque

RésuméIntroductionLe traitement recommandé des tumeurs trophoblastiques gestationnelles (TTG) à bas risque est une monochimiothérapie, habituellement par méthotrexate. La place de l’hystérectomie en première intention est mal définie dans cette indication.MéthodesÉvaluation de la normalisation des hCG des TTG à bas risque après hystérectomie initiale, enregistrées par le Centre français des maladies trophoblastiques de Lyon, France, entre 1999 et 2013.RésultatsSur les 54 patientes incluses, 43 (80 %) ont été guéries définitivement par une hystérectomie. Aucun critère d’échec n’a pu être mis en évidence de façon significative.ConclusionUne hystérectomie est une option thérapeutique possible des TTG à bas risque en cas de demande de la patiente.AbstractIntroductionSingle agent chemotherapy, most usually methotrexate, is the treatment for low-risk Gestational Trophoblastic Neoplasia (GTN). The role of hysterectomy is not clearly known in this situation.MethodsComplete hCG normalization after hysterectomy was evaluated in case of low-risk GTN, in the French Center for Trophoblastic Disease, Lyon, France, between 1999 and 2013.ResultsForty-three patients out of the fifty-four included (80%) were cured by hysterectomy alone. No criteria were predictive of failure.ConclusionHysterectomy could be an option in certain cases of low-risk GTN, especially on patient’s request.

Chondroid nodule in the female peritoneum arises from normal tissue and not from teratoma or conception product

The pathogenesis of benign-looking cartilaginous tissue within the peritoneum is unknown. Chondroid metaplasia of subcoelomic mesenchyme has been suggested, as has been the case for other gynecological diseases such as endometriosis, peritoneal leiomyomatosis, or gliomatosis peritonei, but has never been proven. Chondroid nodules in the peritoneum may represent either teratomatous tissue, fetal rests from a conception product, or metaplasia of pluripotent mesenchymal cells. Herein, the unique genetic characteristics of ovarian teratomas (homozygous at many polymorphic microsatellite loci) versus normal tissues (heterozygous at the same loci) were used to investigate the origin of chondroid nodules in the peritoneum. DNA samples extracted from paraffin-embedded normal peritoneal tissue and chondroid peritoneal nodules from two patients were studied. In both cases, chondroid and normal tissue showed heterozygosity at each informative microsatellite locus on different chromosomes, with a profile similar to the mother. These results indicate that peritoneal chondroid nodules arise within the peritoneum, presumably from pluripotent mesodermal stem cells, and are not related to teratomatous proliferation, or previous pregnancy. This finding shows once again the plasticity and metaplastic potential of stem cells within the peritoneal cavity.

First-line hysterectomy for women with low-risk non-metastatic gestational trophoblastic neoplasia no longer wishing to conceive

BACKGROUND Low-risk gestational trophoblastic neoplasia (GTN) patients (FIGO score ≤6) are generally treated with single agent chemotherapy (methotrexate or dactinomycin) resulting in a 5-year mortality rate of 0.3%. However, despite these encouraging survival rates, chemotherapy is associated with significant adverse events in most patients. Although it is generally accepted that patients who no longer wish to conceive may be treated by hysterectomy for a hydatidiform mole, the evidence to support this strategy in low-risk GTN patients is lacking. OBJECTIVES To describe the survival, efficacy, and tolerance associated with first-line hysterectomy in low-risk non-metastatic GTN patients. STUDY DESIGN Seventy-four of 1072 low-risk GTN patients treated in the French Center underwent first-line hysterectomy. Patients data with successful first-line hysterectomy were retrospectively compared to those requiring further salvage chemotherapy. RESULTS First-line hysterectomy was followed by hCG normalization in 61 patients (82.4%, 95% confidence interval [CI] 71.8-90.3) without any further salvage chemotherapy, whereas 13 patients required salvage chemotherapy. After multivariate analysis, a FIGO score of 5-6 (exact OR 8.961, 95%CI 1.60-64.96), and the presence of choriocarcinoma (exact OR 14.295, 95%CI 1.78-138.13) were associated with the risk of requiring salvage chemotherapy. CONCLUSION Hysterectomy as a first-line treatment is effective without salvage chemotherapy in 82.4% of women with low-risk non-metastatic GTN and can be presented as an alternative to single-agent chemotherapy when childbearing considerations have been fulfilled. In young patients, this therapeutic option should not be considered because single-agent chemotherapies are curative in nearly 100% of patients while maintaining fertility.

Hysterectomy in case of low-risk gestational trophoblastic neoplasia

RésuméIntroductionLe traitement recommandé des tumeurs trophoblastiques gestationnelles (TTG) à bas risque est une monochimiothérapie, habituellement par méthotrexate. La place de l’hystérectomie en première intention est mal définie dans cette indication.MéthodesÉvaluation de la normalisation des hCG des TTG à bas risque après hystérectomie initiale, enregistrées par le Centre français des maladies trophoblastiques de Lyon, France, entre 1999 et 2013.RésultatsSur les 54 patientes incluses, 43 (80 %) ont été guéries définitivement par une hystérectomie. Aucun critère d’échec n’a pu être mis en évidence de façon significative.ConclusionUne hystérectomie est une option thérapeutique possible des TTG à bas risque en cas de demande de la patiente.AbstractIntroductionSingle agent chemotherapy, most usually methotrexate, is the treatment for low-risk Gestational Trophoblastic Neoplasia (GTN). The role of hysterectomy is not clearly known in this situation.MethodsComplete hCG normalization after hysterectomy was evaluated in case of low-risk GTN, in the French Center for Trophoblastic Disease, Lyon, France, between 1999 and 2013.ResultsForty-three patients out of the fifty-four included (80%) were cured by hysterectomy alone. No criteria were predictive of failure.ConclusionHysterectomy could be an option in certain cases of low-risk GTN, especially on patient’s request.