Gestational and Non-gestational Trophoblastic Neoplasia. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 032/049, April 2022)

Abstract

Purpose The aim was to develop and update a guideline which would improve the quality of care offered to women with gestational and non-gestational trophoblastic disease, a group of diseases characterized by their rarity and biological heterogeneity.

Methods In accordance with the method used to compile S2k-guidelines, the guideline authors carried out a search of the literature (MEDLINE) for the period 1/2020 to 12/2021 and evaluated the recent literature. No key questions were formulated. No structured literature search with methodical evaluation and assessment of the level of evidence was carried out. The text of the precursor version of the guideline from 2019 was updated based on the most recent literature, and new statements and recommendations were drafted.

Recommendations The updated guideline contains recommendations for the diagnosis and therapy of women with hydatidiform mole (partial and complete moles), gestational trophoblastic neoplasia after pregnancy or without prior pregnancy, persistent trophoblastic disease after molar pregnancy, invasive moles, choriocarcinoma, placental site nodules, placental site trophoblastic tumor, hyperplasia at the implantation site und epithelioid trophoblastic tumor. Separate chapters cover the determination and assessment of human chorionic gonadotropin (hCG), histopathological evaluation of specimens, and the appropriate molecular pathological and immunohistochemical diagnostic procedures. Separate chapters on immunotherapy, surgical therapy, multiple pregnancies with simultaneous trophoblastic disease, and pregnancy after trophoblastic disease were formulated, and the corresponding recommendations agreed upon.

Key words

guideline - trophoblastic disease - trophoblastic neoplasia - molar pregnancy - choriocarcinoma

I  Guideline Information

Guidelines program of the DGGG, OEGGG and SGGG

For information on the guidelines program, please refer to the end of the guideline.

Citation format

Gestational and Non-gestational Trophoblastic Neoplasia. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 032/049, April 2022). Geburtsh Frauenheilk 2023; 83: 267–288

Guideline documents

The complete long version in German and a slide version of this guideline together with a list of the conflicts of interest of all of the authors are available on the homepage of the AWMF (http://www.awmf.org/leitlinien/detail/ll/032-049.html).

Guideline authors

See [Tables 1] to [4].

Table 1 Lead author and/or coordinating guideline author.

Author	AWMF professional society
Prof. Dr. C. Tempfer, Bochum	Gynecological Oncology Working Group [Arbeitsgemeinschaft für Gynäkologische Onkologie] (AGO e. V.) of the German Society for Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie und Geburtshilfe] (DGGG) and the German Cancer Society [Deutsche Krebsgesellschaft e. V.] (DKG)
Prof. Dr. L.-C. Horn, Leipzig	German Pathology Society [Deutsche Gesellschaft für Pathologie e. V.] (DGP)

The following professional societies/working groups/organizations/associations stated that they wished to contribute to the guideline text and participate in the consensus conference and nominated representatives to attend the consensus conference ([Table 2]).

Table 2 Representativity of the guideline authors: particiption of target user groups.

DGGG working group (AG)/AWMF/non-AWMF professional society/organization/association
Gynecological Oncology Working Group of the DGGG and DKG [Arbeitsgemeinschaft für gynäkologische Onkologie der DGGG und der DKG] (AGO) – Uterus Organ Commission [Organkommission Uterus]
Professional Association of Gynecologists [Berufsverband der Frauenärzte e. V.] (BVF)
German Society for Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V.] (DGGG)
German Society of Clinical Chemistry and Laboratory Medicine [Deutsche Gesellschaft für Klinische Chemie und Laboratoriumsmedizin e. V.] (DGKL)
German Society of Nuclear Medicine [Deutsche Gesellschaft für Nuklearmedizin e. V.] (DGN)
German Pathology Society [Deutsche Gesellschaft für Pathologie e. V.] (DGP)
German Cancer Society [Deutsche Krebsgesellschaft] (DKG)
Austrian Society for Gynecology and Obstetrics [Österreichische Gesellschaft für Gynäkologie und Geburtshilfe e. V.] (OEGGG)
Swiss Society for Gynecology and Obstetrics [Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe] (SGGG)

II  Guideline Application

Table 3 Representativity of the guideline authors: participation of target patient groups.

AWMF/non-AWMF professional society/organization/association
Federal Association of Womenʼs Self-help After Cancer [Bundesverband Frauenselbsthilfe nach Krebs e. V.]

Table 4 Contributing guideline authors.

Author Mandate holder	DGGG working group (AG)/AWMF/non-AWMF professional society/organization/association
PD Dr. S. Ackermann, Darmstadt	Expert
Prof. Dr. R. Dittrich, Erlangen	German Society of Endocrinology [Deutsche Gesellschaft für Endokrinologie] (DGE)
Dr. J. Einenkel, Leipzig	Expert
Prof. Dr. med. A. Günthert, Luzern	Swiss Society for Gynecology and Obstetrics (SGGG)
Frau H. Haase	Federal Association of Womenʼs Self-help After Cancer
Prof. Dr. med. J. Kratzsch, Leipzig	German Society of Clinical Chemistry and Laboratory Medicine (DGKL)
PD Dr. M. Kreissl, Augsburg	German Society of Nuclear Medicine (DGN)
Prof. Dr. med. S. Polterauer, Wien	Austrian Society for Gynecology and Obstetrics (OEGGG)
Prof. Dr. Dr. A. D. Ebert, Berlin	Professional Association of Gynecologists (BVF)
Prof. Dr. E. Steiner, Rüsselsheim	Expert
Prof. Dr. F. Thiel, Göppingen	Expert
Prof. Dr. Michael Eichbaum, Wiesbaden	Expert
Prof. Dr. Tanja Fehm, Düsseldorf	Expert
Dr. Martin C. Koch, Ansbach	Expert
Dr. Paul Gaß, Erlangen	Expert and guidelines secretariat

Purpose and objectives

The purpose of this guideline is to provide information and advice to women about the diagnosis, treatment and follow-up of trophoblastic disease. The focus is on the differentiated management of different forms of gestational and non-gestational trophoblastic disease. In addition, the recommendations of the guideline aim to provide a basis for decision-making during interdisciplinary tumor conferences in cancer centers.

Targeted areas of patient care

Inpatient and outpatient care.

Target user groups/target audience

The guideline is aimed at all women with gestational and non-gestational trophoblastic disease as well as the following medical professionals: gynecologists in private practice, gynecologists working in hospitals, pathologists, specialists for nuclear medicine, specialists for laboratory medicine, geneticists, nursing staff, radiologists and oncologists specializing in internal medicine.

Adoption and period of validity

The validity of this guideline was confirmed by the executive boards/heads of the participating professional societies/working groups/organizations/associations as well as by the board of the DGGG and the DGGG guidelines commission in February 2022 and was thus approved in its entirety. This guideline is valid from 1st April 2022 through to 30th March 2023. Because of the contents of this guideline, this period of validity is only an estimate. The guideline can be reviewed and updated at an earlier point in time if necessary. If the guideline still reflects the current state of knowledge, its period of validity can be extended.

III  Methodology

Basic principles

The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined as consisting of a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches. This guideline has been classified as S2k.

Grading of recommendations

The grading of evidence based on the systematic search, selection, evaluation and synthesis of an evidence base which is then used to grade the recommendations is not envisaged for S2k guidelines. The various individual statements and recommendations are only differentiated by syntax, not by symbols ([Table 5]).

Table 5 Grading of recommendations (based on Lomotan et al., Qual Saf Health Care 2010).

Description of binding character	Expression
Strong recommendation with highly binding character	must/must not
Regular recommendation with moderately binding character	should/should not
Open recommendation with limited binding character	may/may not

Statements

Expositions or explanations of specific facts, circumstances or problems without any direct recommendations for action included in this guideline are referred to as “statements”. It is not possible to provide any information about the level of evidence for these statements.

Achieving consensus and level of consensus

At structured NIH-type consensus-based conferences (S2k/S3 level), authorized participants attending the session vote on draft statements and recommendations. The process is as follows. A recommendation is presented, its contents are discussed, proposed changes are put forward, and all proposed changes are voted on. If a consensus (> 75% of votes) is not achieved, there is another round of discussions, followed by a repeat vote. Finally, the extent of consensus is determined, based on the number of participants ([Table 6]).

Table 6 Level of consensus based on extent of agreement.

Symbol	Level of consensus	Extent of agreement in percent
+++	Strong consensus	> 95% of participants agree
++	Consensus	> 75 – 95% of participants agree
+	Majority agreement	> 50 – 75% of participants agree
–	No consensus	< 51% of participants agree

Expert consensus

As the term already indicates, this refers to consensus decisions taken specifically with regard to recommendations/statements issued without a prior systematic search of the literature (S2k) or where evidence is lacking (S2e/S3). The term “expert consensus” (EC) used here is synonymous with terms used in other guidelines such as “good clinical practice” (GCP) or “clinical consensus point” (CCP). The strength of the recommendation is graded as previously described in the chapter Grading of recommendations but without the use of symbols; it is only expressed semantically (“must”/“must not” or “should”/“should not” or “may”/“may not”).

IV  Guideline

1  Gestational trophoblastic disease (GTD)

Gestational trophoblastic disease (GTD) includes a cytogenetically and clinically heterogeneous group of symptoms characterized by disordered differentiation and/or proliferation of the trophoblastic epithelium [1], [2]. The morphological classification is based on the World Health Organization (WHO) classification [3]. GTD is differentiated into villous and non-villous GTD, depending on the presence of absence of chorionic villi. Villous and non-villous GTD includes both benign and malignant disease as well as lesions which progress from benign to malignant, for example, persistent postmolar trophoblastic disease.

Consensus-based statement 1.S1
Expert consensus	Level of consensus +++
The morphological diagnosis and classification of GTD must be based on the most recent version of the WHO classification.

In highly developed industrial nations, the prevalence of hydatidiform moles is reported to be 1 per 591 pregnancies [4] and the prevalence of GTD is reported to be 1 per 714 live births [5]. In a population-based Dutch study of 6343 cases with GTD collected over a period of 20 years (1994 to 2013), the incidence increased in the first 10 years, followed by stabilization of the incidence of disease. Overall, the incidence of GTD over a period of 20 years was 1.67 cases/1000 births/year [6]. An increased incidence of GTD was found in younger (10 – 19 years of age) and older (40 – 54 years) women and was also correlated with ethnicity. Black US-American women are over-represented in national registers, and the incidence in Asian women is double that reported for women of Caucasian descent.

Consensus-based statement 1.S2
Expert consensus	Level of consensus +++
Postoperative staging of malignant GTD (e.g., choriocarcinoma, PSTT, ETT) must follow the current TNM classification. FIGO staging is optional.

The indication for chemotherapy is based on the risk stratification of GTD and must also be based on the most recent FIGO risk scoring system. This guideline used the International Federation of Gynecology and Obstetrics (FIGO) risk scoring system, shown in [Table 7] [7].

Table 7 International Federation of Gynecology and Obstetrics (FIGO) risk score.

Score	0	1	2	4
Assessment: 0 – 4 points → low risk; 5 – 6 points → intermediate risk; ≥ 7 points → high risk MP = molar pregnancy; TP = term pregnancy; CHXT = chemotherapy; hCG = human chorionic gonadotropin; GI = gastrointestinal
Age (years)	< 40	≥ 40
Previous pregnancy	MP	miscarriage	TP
Interval between last pregnancy to initiation of CHXT (months)	< 4	4 – 6	7 – 12	> 12
hCG (IU/l)	< 103	103–104	104–105	> 105
Number of metastases	0	1 – 4	5 – 8	> 8
Site of metastasis	lung	spleen/kidney	GI tract	brain, liver
Largest tumor diameter (cm)		3 – 5	> 5
Previous CHXT			Monotherapy	Combination CHXT

Consensus-based recommendation 1.E1
Expert consensus	Level of consensus +++
The risk stratification of GTD must be based on the most recent FIGO risk scoring system.

2  Determination of human chorionic gonadotropin (hCG)

In addition to histological confirmation of trophoblastic disease, determination of serum hCG levels is the most important parameter affecting the choice and duration of therapy and used to assess the efficacy of therapy.

Consensus-based recommendation 1.E2
Expert consensus	Level of consensus +++
When determining hCG levels, it is important to use an assay that cross-reacts strongly with the following six irregular forms of hCG which are specifically produced by GTD: hyperglycosylated hCG, nicked hyperglycosylated hCG, nicked hyperglycosylated hCG without the C-terminal peptide, free beta-hCG, nicked free beta-hCG and beta-core fragment.

The reference range limit for hCG measurements is assay-specific and must not be confused with the assayʼs detection limit (synonyms: sensitivity, lower limit of detection). In cases of persistently low hCG levels, before starting treatment it is important to clarify whether the measured hCG values are above the reference range limit of the assay used for premenopausal non-pregnant women. It should also be noted that the reference range limit for postmenopausal women is slightly higher than that for premenopausal women and is therefore unsuitable for premenopausal patients with GTD.

Consensus-based recommendation 1.E3
Expert consensus	Level of consensus ++
If there is a suspicion of false-positive hCG values, findings may be checked using the following approaches: Test the linearity of the hCG results by diluting the sample or by precipitation with PEG; Use blocking cannula; Parallel determination of hCG in serum and urine; Compare results with those obtained by a second laboratory which uses an appropriate but different assay to determine hCG levels. Monitoring of treatment based on hCG levels must always use the same assay method.

The hCG value is considered negative if the measured hCG value is either below the detection limit of the assay used or within the reference range (normal value) of the assay for healthy, non-pregnant premenopausal women (if the patient is premenopausal) or for healthy postmenopausal women (if the patient is postmenopausal). In exceptional cases, a properly negative value may also be slightly higher than the limit of the reference range.

3  Villous GTD

Consensus-based statement 1.S3
Expert consensus	Level of consensus +++
Villous GTD forms include partial moles, hydatidiform moles and invasive moles.

Consensus-based recommendation 1.E4
Expert consensus	Level of consensus +++
The term “partial hydatidiform mole” should not be used in the morphological diagnosis/report on diagnostic findings to describe a partial mole.

Consensus-based statement 1.S4
Expert consensus	Level of consensus +++
The goal of treatment for partial moles/hydatidiform moles is complete evacuation of the trophoblastic material from the uterine cavity.

Consensus-based recommendation 1.E5
Expert consensus	Level of consensus +
Suction curettage performed under sonographic control must be used to evacuate the trophoblastic material from the uterine cavity.

Consensus-based recommendation 1.E6
Expert consensus	Level of consensus +++
Units of red cell concentrate must be on hand during curettage of a partial mole/hydatidiform mole.

Consensus-based recommendation 1.E7
Expert consensus	Level of consensus +++
The risk of perforation and bleeding is higher because the uterus is relaxed. Uterotonic agents may be used in cases with heavy bleeding. A hysterectomy must only be carried out in cases with life-threatening hemorrhage.

Consensus-based statement 1.S5
Expert consensus	Level of consensus +++
No anti-D immunoglobulin is required in cases with partial mole/hydatidiform mole, as there is no expression of the RhD antigen.

Consensus-based recommendation 1.E8
Expert consensus	Level of consensus +++
Because of the risk of developing persistent GTD (0.5 – 4%), regular weekly testing of serum hCG must be done after a partial mole has been diagnosed until the results for hCG are negative (i.e., negative hCG levels in at least two consecutive tests).

Consensus-based recommendation 1.E9
Expert consensus	Level of consensus +++
Because of the risk of developing persistent GTD (16 – 24%), weekly monitoring of hCG must be carried out after a hydatidiform mole has been diagnosed. After the hCG level is found to be negative (at least two consecutive negative hCG tests), monthly monitoring of hCG must be carried out for at least 6 months after curettage. Patients must use hormonal contraceptives. Combined oral preparations may be used.

Consensus-based recommendation 1.E10
Expert consensus	Level of consensus +++
In cases of twin molar pregnancy or women older than 45 years or if it takes more than 8 weeks until the hCG level is negative, monitoring of hCG every three months should be carried out for a further 30 months after the hCG level has been found to be negative.

3.1  Persistent trophoblastic disease

Consensus-based recommendation 1.E11
Expert consensus	Level of consensus +++
If hCG values are persistently high after curettage and diagnosis of a partial mole/hydatidiform mole, re-curettage under sonographic control may be carried out to avoid the necessity of chemotherapy, especially if hCG values are lower than 1000 IU/l. After repeat diagnosis of a partial mole and re-curettage, weekly monitoring of hCG levels must be carried out until the hcG level is found to be negative (i.e., at least 2 consecutive negative hCG tests).

Consensus-based recommendation 1.E12
Expert consensus	Level of consensus +++
Prophylactic chemotherapy must not be administered after curettage of a hydatidiform mole if hCG levels are decreasing or negative.

Consensus-based statement 1.S6
Expert consensus	Level of consensus +
The following criteria must be present for a diagnosis of persistent villous GTD (persistent postmolar trophoblastic disease): Four or more consecutive hCG tests where results show that hCG levels have plateaued (cf. chapter 2 for the definition of the term “plateau”), or An increase in hCG levels (cf. chapter 2 for the definition of the term “increase”) over 2 consecutive measurements (Day 0 and Day 7), or persistent hCG levels over a period of 6 months.

Consensus-based recommendation 1.E13
Expert consensus	Level of consensus ++
If the criteria for a diagnosis of persistent villous GTD are present, in addition to a gynecological examination with palpation to exclude or detect metastasis, the following imaging examinations must be carried out: CT of the thorax and abdomen, transvaginal ultrasound, MRI of the brain. FDG-PET/CT may be carried out if diagnostic imaging is suspicious for metastasis.

Consensus-based recommendation 1.E14
Expert consensus	Level of consensus +++
Chemotherapy must be administered (unless there is an option of carrying out re-curettage) if persistent villous GTD is diagnosed.

3.2  Chemotherapy for low and intermediate risk GTD

Consensus-based recommendation 1.E15
Expert consensus	Level of consensus ++
The drug of choice for low-risk cases (FIGO score < 5; cf. [Table 7]) is methotrexate 50 mg administered by IM injection on days 1, 3, 5, 7 with folic acid 15 mg administered PO on days 2, 4, 6, 8 (cf. Table 15 in the long version). If the patient develops methotrexate resistance (increase or plateauing of hCG levels – for definitions, cf. chapter 1.5 in the long version), treatment must be switched to actinomycin D therapy (1.25 mg/m2 every 2 weeks) or polychemotherapy (EMA/CO regimen) (cf. Tables 15 and 16 in the long version).

Consensus-based recommendation 1.E16
Expert consensus	Level of consensus ++
The drug of choice for cases with intermediate risk (FIGO score 5 – 6; cf. [Table 7]) is methotrexate 50 mg administered by IM injection on days 1, 3, 5, 7 every 2 weeks and folic acid 15 mg administered PO on days 2, 4, 6, 8 (cf. Table 15 in the long version). However, cases with a FIGO score of 5 – 6 and simultaneous distant metastasis and/or hCG > 411000 IU/l and/or a diagnosis of choriocarcinoma must be treated with polychemotherapy (EMA/CO regimen) (cf. Tables 15 und 16 in the long version).

Consensus-based recommendation 1.E17
Expert consensus	Level of consensus +++
If patients are treated with mono-chemotherapy, they must receive 3 consolidation cycles of mono-chemotherapy after hCG levels are no longer detectable (i.e., at least three consecutive weekly measurements of hCG, with hCG levels below the detection limit).

Consensus-based recommendation 1.E18
Expert consensus	Level of consensus +++
If hCG levels are no longer detectable after completion of chemotherapy (i.e., at least three consecutive weekly measurements of hCG, with hCG levels below the detection limit), hCG levels must be monitored and measured once a month for one year.

3.3  Methotrexate resistance

Consensus-based recommendation 1.E19
Expert consensus	Level of consensus +
The following criteria must be present to diagnose methotrexate resistance: Four or more consecutive hCG tests where results show that hCG levels have plateaued (cf. chapter 2 for the definition of the term “plateau”), or An increase in hCG levels (cf. chapter 2 for the definition of the term “increase”)

Consensus-based recommendation 1.E20
Expert consensus	Level of consensus ++
In patients with chemotherapy resistance, re-staging must be done to search for metastasis and must include a gynecological examination with palpation, transvaginal ultrasound, CT of the thorax and abdomen and MRI of the brain. FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above diagnostic imaging.

Consensus-based recommendation 1.E21
Expert consensus	Level of consensus ++
The treatment of choice for cases with MTX resistance is another mono-chemotherapy with actinomycin D (1.25 mg/m2 repeated every 2 weeks). Polychemotherapy according to the EMA-CO regimen may be administered in the event that one of the two mono-chemotherapy regimens fails or if patients have a FIGO score > 7 at re-staging.

Consensus-based recommendation 1.E22
Expert consensus	Level of consensus ++
Polychemotherapy according to the EMA-CO regimen must be administered if both mono-chemotherapy regimens (MTX and actinomycin D) fail (cf. Table 16 in the long version).

Consensus-based recommendation 1.E23
Expert consensus	Level of consensus ++
Platinum-based regimens (BEP/carboplatin + paclitaxel/TP-TE/EMA-EP) must be used if EMA-CO chemotherapy fails, (cf. Table 16 in the long version).

3.4  Chemotherapy for high-risk GTD

Consensus-based recommendation 1.E24
Expert consensus	Level of consensus +++
High-risk cases (FIGO score ≥ 7; [Table 7]) must receive chemotherapy according to the EMA-CO regimen (cf. Table 16 in the long version).

Consensus-based statement 1.S7
Expert consensus	Level of consensus +++
Induction chemotherapy with 1 to 3 cycles of etoposide 100 mg/m2 on days 1 and 2 and cisplatin 20 mg/m2 on days 1 and 2, q7, may reduce early (< 4 weeks after initiation of therapy) hemorrhage-related mortality of high-risk patients with a FIGO score > 12.

Consensus-based recommendation 1.E25
Expert consensus	Level of consensus ++
During polychemotherapy according to the EMA-CO regimen, hCG levels must be measured out before the start of each cycle. If hCG levels plateau or increase, the patient must be switched to multi-agent therapy with EMA-EP or BEP (cf. Table 16 in the long version). Alternative treatments are the TP-TE regimen or a carboplatin-paclitaxel regimen.

Consensus-based recommendation 1.E26
Expert consensus	Level of consensus +
Chemotherapy must be continued until hCG levels are found to be negative (at least three consecutive weekly measurements of hCG, with hCG levels below the detection limit). Failure to complete chemotherapy increases the risk of therapy resistance. Once negative hCG levels have been achieved, up to three additional EMA-CO chemotherapy cycles should be administered for consolidation. Consolidation cycles are not recommended for patients treated with the BEP regimen.

Consensus-based recommendation 1.E27
Expert consensus	Level of consensus +++
In patients with chemotherapy resistance, re-staging must be done to search for metastasis and must include gynecological examination with palpation, transvaginal ultrasound, CT of the thorax and abdomen and MRI of the brain. FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above diagnostic imaging.

Consensus-based recommendation 1.E28
Expert consensus	Level of consensus +
If hCG levels are no longer detectable after the completion of chemotherapy (i.e., at least three consecutive weekly measurements of hCG, with hCG levels below the detection limit), hCG levels must be monitored and measured once a month for one year. During this period patients must take oral hormonal contraceptives. Combined oral preparations or progestogen preparations may be used.

3.5  Invasive moles

Consensus-based recommendation 1.E29
Expert consensus	Level of consensus +++
Staging is based on CT of the thorax, CT of the abdomen, MRI of the brain, transvaginal ultrasound and gynecological examination with palpation. FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above diagnostic imaging.

Consensus-based recommendation 1.E30
Expert consensus	Level of consensus ++
Patients with invasive mole must be treated with chemotherapy. The drug of choice for low-risk cases (FIGO score < 7; [Table 7]) is methotrexate 50 mg administered by IM injection on days 1, 3, 5, 7 and folic acid 15 mg administered PO on days 2, 4, 6 (cf. Table 15 in the long version). High-risk cases (FIGO score ≥ 7; [Table 7]) must receive chemotherapy according to the EMA-CO regimen (cf. Table 16 in the long version). Chemotherapy may not be necessary for low-risk patients who have undergone hysterectomy.

Consensus-based statement 1.S8
Expert consensus	Level of consensus +++
Monitoring of hCG levels during and after therapy is done according to the same standards used for hydatidiform mole (cf. 1.6.2 in the long version).

4  Non-villous GTD

4.1  Placental site nodules (PSN)

Consensus-based statement 1.S9
Expert consensus	Level of consensus +++
Curettage, usually consisting of complete removal of the lesion, is the treatment of choice for PSN.

Consensus-based recommendation 1.E31
Expert consensus	Level of consensus +++
PSN is a benign lesion. Follow-up based on measurement of hCG levels is not required.

4.2  Exaggerated placental site (EPS)

Consensus-based recommendation 1.E32
Expert consensus	Level of consensus +++
Isolated EPS without hydatidiform mole must not be treated with chemotherapy. Postoperative monitoring of hCG levels must only be done if there are clinical indications such as persistent vaginal bleeding.

Consensus-based recommendation 1.E33
Expert consensus	Level of consensus +++
If EPS is diagnosed in combination with partial mole or hydatidiform mole, follow-up must adhere to the same standards used for partial mole or hydatidiform mole.

4.3  Placental site trophoblastic tumor (PSTT)

Consensus-based recommendation 1.E34
Expert consensus	Level of consensus +++
A simple hysterectomy must be carried out if PSTT is diagnosed in the curettage material.

Consensus-based recommendation 1.E35
Expert consensus	Level of consensus +++
In addition to gynecological examination with palpation, the following diagnostic imaging is necessary to detect or exclude metastasis: CT of the thorax and abdomen, transvaginal ultrasound, MRI of the brain. FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above diagnostic imaging.

Consensus-based recommendation 1.E36
Expert consensus	Level of consensus +++
Chemotherapy is necessary to treat FIGO stages II to IV and should consist of either the EMA-CO regimen (cf. Table 16 in the long version) or the EP/EMA regimen (cf. Table 16 in the long version). The BEP regimen may be used if the EMA-CO and EP/EMA regimens are unsuccessful.

Consensus-based recommendation 1.E37
Expert consensus	Level of consensus +++
It is important to differentiate PSTT from EPS. Before deciding on a hysterectomy, the opinion of a second pathologist should be obtained for premenopausal patients wanting to have children.

Consensus-based recommendation 1.E38
Expert consensus	Level of consensus +++
If hCG levels are no longer detectable after the completion of chemotherapy (at least three consecutive weekly measurements of hCG, with hCG levels below the detection limit), hCG levels must be monitored and measured once a month for one year.

4.4  Epithelioid trophoblastic tumor (ETT)

Consensus-based statement 1.S10
Expert consensus	Level of consensus +++
Hysterectomy is the treatment of choice for ETT. As with PSTT, polychemotherapy is indicated if metastasis is present at the initial diagnosis of ETT.

Consensus-based recommendation 1.E39
Expert consensus	Level of consensus +++
If hCG levels are no longer detectable after the completion of chemotherapy (i.e., at least three consecutive weekly measurements of hCG, with hCG levels below the detection limit), hCG levels must be monitored and measured once a month for one year.

4.5  Choriocarcinoma (CCA)

Consensus-based recommendation 1.E40
Expert consensus	Level of consensus ++
As with hydatidiform mole, suction curettage under sonographic control must be carried out if there is a suspicion of choriocarcinoma.

Consensus-based recommendation 1.E41
Expert consensus	Level of consensus +++
Units of red cell concentrate must be on hand during curettage.

Consensus-based recommendation 1.E42
Expert consensus	Level of consensus +++
Staging after histological confirmation of choriocarcinoma is based on gynecological examination with palpation, transvaginal ultrasound, CT of the thorax and abdomen and MRI of the brain. FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above diagnostic imaging.

Consensus-based recommendation 1.E43
Expert consensus	Level of consensus ++
Chemotherapy must be carried out after histological confirmation of choriocarcinoma. The drug of choice for low-risk cases with a FIGO score < 5 (cf. [Table 7]) is methotrexate 50 mg administered by IM injection on days 1, 3, 5, 7 and folic acid 15 mg administered PO on days 2, 4, 6 (cf. Table 15 in the long version). If the patient develops methotrexate resistance (increase or plateauing; see chapter 2 for the definition of hCG plateau), treatment should be switched to actinomycin D therapy or polychemotherapy (cf. Table 15 and 16 in the long version).

Consensus-based recommendation 1.E44
Expert consensus	Level of consensus ++
Chemotherapy must be carried out after histological confirmation of choriocarcinoma. The treatment of choice for intermediate-risk cases (FIGO score 5 or 6; cf. [Table 7]) is polychemotherapy using the EMA-CO regimen (cf. Table 16 in the long version).

Consensus-based recommendation 1.E45
Expert consensus	Level of consensus +++
Treatment for high-risk patients (FIGO score ≥ 7; [Table 7]) must consist of chemotherapy using the EMA-CO regimen (cf. Table 16 in the long version).

Consensus-based statement 1.S11
Expert consensus	Level of consensus +++
Induction chemotherapy consisting of 1 to 3 cycles of etoposide 100 mg/m2 on days 1 and 2, q7, and cisplatin 20 mg/m2 on days 1 and 2, q7, may reduce early (< 4 weeks after initiation of therapy) hemorrhage-related mortality of high-risk patients with a WHO score > 12 ([Table 7]).

Consensus-based recommendation 1.E46
Expert consensus	Level of consensus +++
Re-staging to search for metastasis must be done if the patient develops chemotherapy resistance, with re-staging based on gynecological examination with palpation, transvaginal ultrasound, CT of the thorax and abdomen and MRI of the brain. FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above diagnostic imaging.

Consensus-based recommendation 1.E47
Expert consensus	Level of consensus +++
Chemotherapy must be continued until hCG levels are negative (at least three consecutive weekly measurements of hCG, with hCG levels below the detection limit). Failure to complete chemotherapy increases the risk of therapy resistance. Once negative hCG levels have been achieved, up to three additional EMA-CO chemotherapy cycles should be administered for consolidation. Consolidation cycles are not recommended for patients treated with the EMA-EP or BEP regimen.

Consensus-based recommendation 1.E48
Expert consensus	Level of consensus +++
After the completion of therapy, hCG levels levels must be monitored and measured once a month for one year.

4.6  Multiple pregnancy and GTD

Cases of multiple pregnancy with GTD and one healthy twin have been reported in the literature. In a series of 77 cases with hydatidiform mole and one healthy twin, the pregnancy was terminated in 24 cases [8]. Of the 53 women who continued their pregnancy, 23 had a spontaneous miscarriage and two developed severe preeclampsia with subsequent termination of the pregnancy. Twenty-four of the remaining 28 women had a live birth. Irrespective of the pregnancy outcome, 15/77 women had chemotherapy for persistent trophoblastic disease. Lin et al. reported on 72 cases with complete mole and a healthy co-twin [9]. Ten pregnancies were terminated, 35/62 cases had a live birth. The rate of postoperative or postpartum gestational trophoblastic neoplasia (GTN) was 46%. In a review of the literature, Suksai et al. identified a total of 204 cases in the literature of complete mole with a second fetus. The live birth rate was 78/204 (38%). Low hCG levels were a predictor for live birth [10].

Zilberman et al. (14 studies; n = 244; complete hydatidiform mole + normal fetus) calculated a maternal rate of complications of 80%, a live birth rate of 50% and a rate of subsequent GTN of 34% [11].

5  Immunotherapy

GTD shows a high expression of the transmembrane protein programmed cell death-ligand 1 (PD-L1), which binds to the T-cell inhibitory receptor (programmed death protein 1 [PD-1]). Treatment with the immune checkpoint inhibitor pembrolizumab, a monoclonal antibody which binds to the PD-1 receptor, was investigated in patients with chemotherapy-resistant GTD [12]. A total of four patients with chemotherapy resistance after several lines of combination chemotherapy were treated with pembrolizumab 2 mg/kg every 3 weeks. After remission was achieved, patients received a further five consolidation cycles. Therapy was well tolerated. Complete remission was observed in three of four patients after the end of therapy, and remission persisted for between five and 24 months after completion of therapy. A recent review of seven patients with previously treated, chemotherapy-resistant GTD found that 6/7 patients responded to immunotherapy with pembrolizumab. A complete response was observed in five patients [13]. Other case studies have reported similar successes in patients, some of whom had extensive prior treatment. A single-arm prospective study investigated the use of the PD-L1 antibody avelumab in patients with low-risk GTN after previous mono-chemotherapy with MTX. Patients were given avelumab 10 mg/kg every two weeks until hCG levels had normalized, followed by three consolidation cycles. 8/15 patients had a complete response to therapy [14].

6  Pregnancy After GTD

Pregnancy after GTD is possible and is not associated with an unfavorable maternal, fetal or neonatal prognosis. It should be noted that there is a risk of recurrence. Gadducci et al. specifically calculated the risk of recurrence of GTD as 0.7 to 2.6% after a previous instance of GTD and as 10% after two GTDs [15]. The live birth rate of women with a history of GTD is 75%. There is no increase in the rate of congenital malformations (1.8%); however, there may a slightly higher risk of intrauterine fetal death [16]. In a systematic review of 18 studies on fertility after GTD, Garcia et al. reported that there was no evidence for a lower fertility after GTD, but there was a higher risk of miscarriage for pregnancies occurring less than six months after the completion of GTD therapy and a higher risk of intrauterine fetal death [17].

Once patients have completed chemotherapy for GTD, the issue of potential long-term side effects on fertility must be considered. This issue is compounded by the possibility of a second malignancy caused by the treatment. The review by Gaducci et al. reported a higher risk of myeloid leukemia, which increased depending on the cumulative dose of etoposide [18]. The genotoxicity of MTX and EMA-CO is low. In an analysis of 12 women treated with MTX and 34 women treated with EMA-CO, 12/12 (100%) and 32/34 (97%) women, respectively, had regular menstrual cycles after completion of chemotherapy [19].

7  Evaluation of Specimens

Consensus-based recommendation 4.E49
Expert consensus	Level of consensus +++
The report on findings must include the type of GTD.

Consensus-based recommendation 4.E50
Expert consensus	Level of consensus +++
The morphological diagnostic workup must ensure that alle therapeutically and prognostically relevant parameters are ascertained. Findings must be reported according to the valid WHO classification of tumors, the current TNM staging system and the R classification (UICC).

Consensus-based recommendation 4.E51
Expert consensus	Level of consensus +++
The findings report for a hysterectomy carried out for GTD must including the following information: Type of GTD according to the WHO classification Presence/absence of lymph node or vascular invasion (L- and V-status) Presence/absence of perineural invasion (Pn-status) Staging (pTNM and FIGO) Three-dimensional tumor size in cm3 Minimal distance to vaginal margin in cm, if relevant R classification (UICC)

8  Information for Patients

Consensus-based recommendation 5.E52
Expert consensus	Level of consensus +++
When appropriate relevant sources (print or internet media) are used to inform patients, the information should be compiled in accordance with defined quality criteria for healthcare information. The information should be provided to patients to support them to make self-determined decisions for or against medical measures by communicating the risks in a generally understandable form (e.g., information about the reduction of absolute risk).

Consensus-based recommendation 5.E53
Expert consensus	Level of consensus +++
The patient must be offered the option of including her partner or family members in talks or discussions.

Consensus-based recommendation 5.E54
Expert consensus	Level of consensus +++
The patientʼs individual preferences, requirements, worries and anxieties must be identified during the talk with the doctor and taken into account. If the patient requires several discussions for this, she must be offered the opportunity to have more discussions.

Consensus-based recommendation 5.E55
Expert consensus	Level of consensus +++
The patient should be offered psychosocial and psycho-oncological support for psychological and sexual problems and problems with her partner.

Consensus-based recommendation 5.E56
Expert consensus	Level of consensus +++
Medical-oncological rehabilitation is designed specifically to treat disorders which arise subsequent to the disease and its treatment. All patients must be informed and advised about their statutory options to apply for and make use of rehabilitation measures.

Conflict of Interest/Interessenkonflikt

The conflicts of interests of all of the authors are listed in the long version of the guideline./Die Interessenkonflikte der Autoren sind in der Langfassung der Leitlinie aufgelistet.

• References/Literatur

• 1 Ngan S, Seckl MJ. Gestational trophoblastic neoplasia management: an update. Curr Opin Oncol 2007; 19: 486-491
• 2 Garner EI, Goldstein DP, Feltmate CM. et al. Gestational trophoblastic disease. Clin Obstet Gynecol 2007; 50: 112-122
• 3 Hui P, Baergen R, Cheung A, Fukunaga M, Gersell D, Lage J, Ronnett B, Sebire N, Wells M. Gestational trophoblastic Disease. In: Kurman RJ, Carcangiu ML, Herrington CS, Young RH. eds. WHO Classification of Tumours of female reproductive Organs. Lyon: IARC; 2014: 158-167
• 4 Savage P, Williams J, Wong SL. et al. The demographics of molar pregnancies in England and Wales from 2000–2009. J Reprod Med 2010; 55: 341-345
• 5 Tham BW, Everard JE, Tidy JA. et al. Gestational trophoblastic disease in the Asian population of Northern England and North Wales. BJOG 2003; 110: 555-559
• 6 Eysbouts YK, Bulten J, Ottevanger PB. et al. Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study. Gynecol Oncol 2016; 140: 70-75
• 7 Ngan HY, Bender H, Benedet JL. et al. FIGO Committee on Gynecologic Oncology. Gestational trophoblastic neoplasia, FIGO 2000 staging and classification. Int J Gynaecol Obstet 2003; 83 (Suppl. 01) 175-177
• 8 Sebire NJ, Foskett M, Paradinas FJ. et al. Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 2002; 359: 2165-2166
• 9 Lin LH, Maesta I, Braga A. et al. Multiple pregnancies with complete mole and coexisting normal fetus in North and South America: A retrospective multicenter cohort and literature review. Gynecol Oncol 2017; 145: 88-95
• 10 Suksai M, Suwanrath C, Kor-Anantakul O. et al. Complete hydatidiform mole with co-existing fetus: Predictors of live birth. Eur J Obstet Gynecol Reprod Biol 2017; 212: 1-8
• 11 Zilberman Sharon N, Melcer Y, Maymon R. Is a Complete Hydatidiform Mole and a Co-existing Normal Fetus an Iatrogenic Effect?. Isr Med Assoc J 2019; 21: 653-657
• 12 Ghorani E, Kaur B, Fisher RA. et al. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia. Lancet 2017; 390: 2343-2345
• 13 Choi MC, Oh J, Lee C. Effective anti-programmed cell death 1 treatment for chemoresistant gestational trophoblastic neoplasia. Eur J Cancer 2019; 121: 94-97
• 14 You B, Bolze PA, Lotz JP. et al. Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance to Single-Agent Chemotherapy: Cohort A of the TROPHIMMUN Phase II Trial. J Clin Oncol 2020; 38: 3129-3137
• 15 Gadducci A, Lanfredini N, Cosio S. Reproductive outcomes after hydatiform mole and gestational trophoblastic neoplasia. Gynecol Endocrinol 2015; 31: 673-678
• 16 Tranoulis A, Georgiou D, Sayasneh A. et al. Gestational trophoblastic neoplasia: a meta-analysis evaluating reproductive and obstetrical outcomes after administration of chemotherapy. Int J Gynecol Cancer 2019; 29: 1021-1031
• 17 Garcia MT, Lin LH, Fushida K. et al. Pregnancy outcomes after chemotherapy for trophoblastic neoplasia. Rev Assoc Med Bras (1992) 2016; 62: 837-842
• 18 Gadducci A, Cosio S, Fanucchi A. et al. Prognosis of Patients with Gestational Trophoblastic Neoplasia and Obstetric Outcomes of Those Conceiving After Chemotherapy. Anticancer Res 2016; 36: 3477-3482
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Publikationsverlauf

Eingereicht: 12. Juli 2022

Angenommen nach Revision: 16. Juli 2022

Artikel online veröffentlicht:
09. März 2023