Gestational Trophoblastic Disease - School of Medicine · 2020-06-03 · • Gestational Trophoblastic Disease (GTD): Benign and malignant tumors of the uterus, arising from placental

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Gestational Trophoblastic Disease

What you need to know for the “once-every-10-years”patient Marisa Adelman, MD


Definition

• Gestational Trophoblastic Disease (GTD): Benign and malignant tumors of the uterus, arising from placental tissue.

• Hydatidiform Moles (HM): benign, premalignant disease • Complete mole• Partial mole

• Gestational Trophoblastic Neoplasia (GTN): malignant disease• Invasive mole • Choriocarcinoma• Intermediate trophoblastic tumors (ITT)

• Placental site trophoblastic tumor (PSTT)• Epithelioid trophoblastic tumor (ETT)


Classification

GTD

HM80%

Complete mole(30% all GTD)

Partial mole(40% all GTD)

Persistent mole(non-invasive)

GTN20%

Invasive mole15%

Choriocarcinoma ITT

PSTT ETT


Epidemiology

Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study. Eybouts YK, et al. Gynecol Oncol 2016;140:70-5.

GTD subtype Incidence

Overall 1.67 per 1,000 deliveries

Hydatidiform mole 1.36 per 1,000 deliveries

Complete hydatidiform mole 0.52 per 1,000 deliveries

Partial hydatidiform mole 0.67 per 1,000 deliveries

Choriocarcinoma 3 per 100,000 deliveries

Placental site trophoblastic tumor 0.9 per 100,000 deliveries

Epithelioid trophoblastic tumor 0.1 per 100,000 deliveries


Epidemiology

Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study. Eybouts YK, et al. Gynecol Oncol 2016;140:70-5.; Risk of partial and complete hydatidiform molar pregnancy in relation to maternal age. Sebire NJ, et al. BJOG. 2002;109:99-102.

• Age may play a role in the risk of molar pregnancy.• Increased relative risk of molar pregnancy at the extremes of maternal age

(≥45 years old and ≤15 years old)• The risk is greatest for complete moles at the upper extreme of maternal age.

• May be due to fertilization of an abnormal oocyte at the beginning and end of the female reproductive period.

• May observe chromosomally deficient oocytes, allowing either dispermic fertilization, or monospermic nuclear duplication.

• The majority of molar pregnancies, however, occur in the middle of the reproductive period.


Genetics• Complete mole

• Result from abnormal fertilization of an ovum lacking nuclear DNADuplication of a single sperm genome Dispermy

• Partial mole• Results from abnormal fertilization of an ovum retaining its nuclear DNA

Duplication of a single sperm genome (uncommon)Dispermy


Genetics: complete mole

23 X

Empty ovum

Chromosome duplication46 XX46 XX Diploid

Monospermic

23 X or Y

Empty ovum

46 XX46 XX

DiploidDispermic

23 X or Y

46 XX46 XY

+

+


Genetics: partial mole

23 X or Y

+ 46 XX69 XXY Triploid

Dispermic23 X or Y

+

46 XX69 XYY

46 XX69 XXX

23 X

Rare

Most common


Postmolar GTD Develops in 15-20% of complete molesDevelops in 1-5% of partial moles

• Invasive mole: • Arises from extension of villous trophoblast (from HM) into the myometrium via tissue or venous channels.

• Choriocarcinoma• Arises from villous trophoblast following various types of pregnancy:

• HM (50%)• Term or preterm pregnancy (25%)• Tubal pregnancy or abortion (25%)

• Intermediate trophoblastic tumors• Arises from interstitial trophoblast at the placental implantation site following mostly non-molar pregnancies.

• ETT is a rare variant of PSTT, resulting in neoplastic transformation of intermediate trophoblast years after a term delivery.

• Has a greater propensity for lymphatic spread. • Metastases are noted in 30-50% of cases, most commonly to the lungs.


Early placental development

Avagliano, L. (2016, August 12). Histology of the Human Placenta. Retrieved from https://www.semanticscholar.org

This occurs between the morula and blastocyst stage of development.

https://www.semanticscholar.org/




The syncytiotrophoblast penetrates the uterine wall

The cytotrophoblast differentiates beneath the syncytiotrophoblast





The cytotrophoblast undergo rapid division, expanding the syncytiotrophoblast





Extravillous trophoblast invades the maternal decidua

Formation of cytotrophoblastic anchoring columns.



Correlation with GTN• Villous trophoblast

• Cytotrophoblast invasive mole, choriocarcinoma• Syncytiotrophoblast invasive mole, choriocarcinoma

• Extravillous trophoblast• Intermediate trophoblast PSTT and ETT


Workup of HM• H&P• Pelvic ultrasound• Quantitative hCG• CBC• Liver, renal, and thyroid function tests• Blood type and screen• Chest x-ray

Case courtesy of Dr Rengarajan R, Radiopaedia.org, rID: 23843; Case courtesy of Dr Avni K P Skandhan, Radiopaedia.org, rID: 25306


Treatment of HM• Suction D&C (preferably under ultrasound guidance)

• Hysterectomy can be considered as an alternative if not desiring future fertility

• Rho (D) administration where appropriate• Use of uterotonics during and following the procedure• Histopathologic review and possible genetic testing to confirm diagnosis

• Flow cytometry to determine ploidy• Differentiate complete from partial moles

• Biomarkers to identify the absence of paternally imprinted, but maternally expressed genes

• Differentiate between complete moles and non-molar hydropic abortions

Genest DR, Dorfman DM, Castrillon DH. Ploidy and imprinting in hydatidiform moles: complementary use of flow cytometry and immunohistochemistry of theimprinted gene product p57KIP2 to assist molar classification. J Reprod Med 2002;47:342-46.


Prophylactic chemotherapy for HM• May reduce the incidence of postmolar GTN by 3-8%• May be considered in women with complete HM, at high risk for

malignant transformation:• Age > 40 years old• hCG levels >100,000 mIU/mL• Excessive uterine enlargement• Theca lutein cysts > 6 cm.

• NCCN Guidelines: prophylactic methotrexate or dactinomycin can be considered for patients deemed at high risk for post-molar GTN.

Kim DS, Moon H, Kim KT, et al. Effects of prophylactic chemotherapy for persistent trophoblastic disease in patients with complete hydatidiform mole. ObstetGynecol. 1986;67:690–94. Limpongsanurak S. Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med. 2001;46:110–16. Wang Q, FuJ, Hu L, et al. Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia. Cochrane Database of Systematics Reviews2017;9.


Prophylactic chemotherapy for HM

• Although it may reduce the risk of progression to GTN in women who are at high-risk of malignant transformation, it also:

• May increase drug resistance, • May delay treatment of GTN• Would expose women to toxic side effects

• Cannot be routinely recommended, and:• Would only reduce the risk of needing full-scale chemotherapy• Would not eliminate the need for monitoring and follow-up

Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia. Wang Q, et al. Cochrane Database of Syst Rev. 2017;9.


Follow-up of HM

• Quantitative hCG monitoring• hCG assay every 1-2 weeks until 3 consecutive normal levels.• hCG asses twice in 3 month intervals following initial normalization• Assay should be capable of detecting all forms of hCG (beta-hCG, core hCG,

nicked-free beta, beta core, hypoglycosylated forms), as the molecules associated with HM tend to be more heterogenous and degraded.

Cole LA. Human chorionic gonadotropin and associated molecules. Expert Rev Mol Diagn 2009;9:51-73. Muller CY, Cole LA. The quagmire of hCGand hCG testing in gynecologic oncology. Gynecol Oncol 2009;112:663-72.


Recurrence, development of GTN

• Risk of recurrence is <2% after a single molar pregnancy• Increased risk of CHM in woman with NLRP7 or KHDC3L gene mutations.

• Reported incidence of GTN after molar pregnancy is 18-29%• 15-20% CM’s• 1-5% PHM’s• 2-3% of HM’s progress to choriocarcinoma

• Once hCG level normalized, recurrent elevation occurs in <1%.

Sebire NJ, Fisher, RA, Foskett M, et al. Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molarpregnancy. Br J Obstet Gynaecol 2003;110:22-26.


Risk of GTN after hCG normalization

• The overall risk of developing GTN after normalization of hCG is approximately 0.3%.

• 0-0.1% risk after a PHM• 0.3-0.6% risk after a CHM• 0-9.5% risk after a multiple pregnancy involving HM

• Patients who required >56 days (8 weeks) to achieve a normal hcg level may have as much as a 10-fold increased risk of developing GTN.

• May consider stopping surveillance:• At the time of normalization, following a PHM.• 6 months after normalization, following a CMH.• 12 months after normalization, following a multiple pregnancy involving HM

Risk of gestational trophoblastic neoplasia after hCG normalization according to hydatidiform mole type. Schmitt S, et al. Gynecol Oncol. 2013 Jul; 130(1):86-9.Gestational trophoblastic neoplasia after spontaneous human chorionic gonadotropin normalization following molar pregnancy evacuation. Braga A, et al.Gynecol Oncol. 2015.139(2):283-87.


Post-molar GTN

• Defined as:• hCG levels plateau for 4 consecutive values over ≥ 3 weeks• hCG levels rise ≥ 10% 3 values over ≥ 2 weeks• hCG elevation persists ≥ 6 months after molar evacuation

• Workup:• H&P• Pelvic ultrasound• CBC, liver/renal/thyroid function testing, hCG assay• Chest x-ray• Chest/abdominal/pelvic CT (if pulmonary metastasis present)• Brain MRI (if pulmonary metastasis present)• Do not biopsy any lesions of the lower genital tract due to risk of hemorrhage


GTN Staging


GTN Prognostic score


Post-molar GTN

• NCCN Guidelines: Repeat D&C or hysterectomy can be considered for (non-metastatic) persistent post-molar GTN.

• Post-surgical surveillance:• hCG assay ever 2 weeks until 3 consecutive normal levels.• hCG assay monthly for 6 months following normalization.


Second curettage for low-risk disease

• 40% surgical cure with second curettage, avoiding the need for chemotherapy.

• Success of second curettage could not be predicted with statistical significance on the basis of age, WHO risk score, registration hCG, or ultrasound findings.

• Extremes of patient age may have value in predicting failure.• Unlikely to benefit patients with a risk score >4.

• Second curettage might identify an alternative GTD type, which might necessitate a different treatment strategy.

Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia. Osborne RJ Obstet Gynecol 2016;128:535-42.


Hysterectomy for treatment of HM

• 82.4% of low-risk, non-metastatic GTN patients were successfully treated with first-line hysterectomy.

• 17.6% required salvage chemotherapy.

• A FIGO score of 5-6 (versus 1-4) was significantly associated with risk of requiring salvage chemotherapy.

• Would not consider this therapeutic approach in young patients, as single-agent chemotherapy is curative in nearly 100% of patients.

The added value of hysterectomy in the management of gestational trophoblastic neoplasia. Eysbouts YK, et al. Gynecol Oncol 2017;145: 536-542.First-line hysterectomy for women with low-risk non-metastatic gestational trophoblastic neoplasia no longer wishing to conceive. Bolze PA, et al.Gynecol Oncol 2018;150:282-287.

.


Hysterectomy for treatment of HM

• When to consider primary hysterectomy:• Older patients with localized disease and no desire for fertility• Chemotherapy resistant disease, particularly when localized.• Patients with widespread metastatic disease, to remove chemotherapy resistant

bulk tumor.

• Hysterectomy may also play a role in management of life-threatening complications, including abdominal or vaginal hemorrhage.

The added value of hysterectomy in the management of gestational trophoblastic neoplasia. Eysbouts YK, et al. Gynecol Oncol 2017;145: 536-542.First-line hysterectomy for women with low-risk non-metastatic gestational trophoblastic neoplasia no longer wishing to conceive. Bolze PA, et al.Gynecol Oncol 2018;150:282-287.

.


Treatment of Low-Risk GTN

• First-line therapy• Single-agent chemotherapy with methotrexate or dactinomycin

• Second-line therapy• If good response to initial chemotherapy:

• Alternate single-agent chemotherapy (methotrexate or dactinomycin)• Hysterectomy and salpingectomy for localized disease.

• If poor response to initial chemotherapy, or rapid rise in hCG level:• Multiagent-chemotherapy (EMA/CO)- same as primary therapy for high-risk disease• Hysterectomy and salpingectomy for localized disease.• Repeat work-up for metastatic disease

• Third-line therapy• For persistent or recurrent disease after EMA-CO:

• Etoposide/platinum-based regimen- same as for incomplete response for high-risk disease• Surgical resection where feasible


Treatment of Low-Risk GTN


Treatment of High-Risk GTN

• Primary chemotherapy• EMA/CO

• Salvage chemotherapy• If good response to initial chemotherapy:

• EMA/EP or EP/EMA• If poor response to initial chemotherapy, or rapid rise in hCG level:

• Etoposide/platinum-based regimen: TP/TE, BEP, VIP









• Induction chemotherapy• Low-dose etoposide/cisplatin prior to EMA/CO• For patients with wide-spread metastatic disease, to avoid tumor collapse, hemorrhage,

metabolic acidosis, septicemia, and multiorgan failure.

• Management of CNS metastases• Whole-brain irradiation• Stereotactic radiosurgery• Craniotomy with surgical excision• Addition of high-dose or intrathecal methotrexate

• Adjuvant Surgery• For chemotherapy resistant disease, particularly of the uterus or lungs.

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Treatment of Intermediate-Risk GTN

• ITTs are relatively chemoresistant• Adverse prognostic factors include:

• Advanced disease stage• Interval from last known pregnancy (≥48 months)

• Hysterectomy with lymph node dissection for localized disease• Metastasectomy for isolated distant disease (particularly lung)• Chemotherapy for metastatic disease or having an adverse prognostic

factor.• Platinum/etoposide-containing regimen: EMA/EP, TP/TE

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Treatment of Intermediate-Risk GTN

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Gestational Trophoblastic Disease - School of Medicine · 2020-06-03 · • Gestational Trophoblastic Disease (GTD): Benign and malignant tumors of the uterus, arising from placental