Gestational trophoblastic neoplasia overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]Sabawoon Mirwais, M.B.B.S, M.D.[3]

Overview

Gestational trophoblastic disease (GTD) includes several rare tumors that occur in the uterus and start in the cells that form the placenta during pregnancy. In 6th century, Aetius of Amida, a physician at Justinian's court came up with the term 'hydatid'. Next mention of 'mole' is from 1276 when Margaret, Countess of Henneberg, delivered approximately 300 babies on Good Friday (the Friday before Easter Sunday). In 1827, Marie Anne Victoire Boivin, a Parisian midwife, proposed her findings of this condition in 'Nouvelles Recherches de la Mole Visiculaire' (News Searches of the Vesicular Mole). In 1840, William Wilton reported a case of invasive mole that was complicated by uterine perforation and fatal internal hemorrhage. In 1867, Richard von Volkmann, a German surgeon, also described a lesion resembling an invasive mole. In 1877, Hans Chiari, an Austrian pathologist, reported three cases of choriocarcinoma. He recognized the tumors as epithelial. In 1888, Max Sanger, a German obstetrician, proposed his theory that these tumors were actually sarcomas ('deciduoma malignum'). In 1890, Pfeiffer, a student of Hans Chiari, re-examined Chiari's cases and added a fourth case. He named them all 'deciduoma malignum'. In 1891, Pestalozza from Italy, reported three cases of a malignantuterine tumor associated with pregnancy. He described these cases as 'sarcoma hemorrhagicum sen infectiosum'. Gestational trophoblastic neoplasia may be classified according to histology into four subtypes: invasive mole, choriocarcinoma, placental-site trophoblastictumor, and epithelioid trophoblastic tumor. Pregnancy occurs when an egg, which is released from the ovary during ovulation, is fertilized by a sperm. Human pregnancy takes approximately 40 weeks. Gestational trophoblastic neoplasia arises from the trophoblastic tissue, which provides nutrients to the embryo and develops into a large part of the placenta. Invasive mole is basically a benign tumor which arises from the invasion of the myometrium of a hydatidiform mole. Choriocarcinoma is a malignant tumor of the trophoblastic epithelium. Placental-site trophoblastic tumor (PSTT), a rare tumor, arises from the implantation site of placenta. Epithelioid trophoblastic tumor (ETT) is basically a rare variant of placental-site trophoblastic tumor (PSTT) which arises from the malignant transformation of chorionic-type intermediate trophoblastic cells. Invasive mole is usually diploid but can also be aneuploid in karyotype. Choriocarcinoma has an aneuploidkaryotype and majority of the cases have a Y chromosome. Complete hydatidiform mole arises when an ovum without maternal chromosomes is fertilized by one sperm which duplicates its DNA, resulting in a 46XX androgenetic karyotype. Partial hydatidiform moles are almost always triploid, resulting from the fertilization of a healthy ovum by two sperms. Abnormal trophoblastic population undergoing hyperplasia and anaplasia can give rise to choriocarcinoma. Gestational type choriocarcinoma arises following a hydatidiform mole, normal pregnancy, or most commonly, abortion. Non-gestational type choriocarcinoma arises from pluripotent germ cells. Placental-site trophoblastic tumor (PSTT) arises from the placental implantation site when the trophoblastic cells infiltrate the myometrium. Epithelioid trophoblastic tumor (ETT) arises from the intermediate trophoblastic cells of chorion.Gestational trophoblastic neoplasia (invasive mole, choriocarcinoma, placental-site trophoblastic tumor [PSTT] and epitheloid trophoblastic tumor [ETT]) should be differentiated from other conditions presenting with similar symptoms and signs such as increase in uterine size, vaginal bleeding and amenorrhea. The differentials include molar pregnancy (complete and partial moles), ovarian tumors, spontaneous abortion, ectopic pregnancy and normal term pregnancy.The reported incidence of choriocarcinoma in the United States is 2 to 7 per 100,000 pregnancies. The U.S. age-standardized (1960 World Population Standard) incidence rate of choriocarcinoma is approximately 0.18/100,000 women between the ages of 15 - 49 years. The prevalence of choriocarcinoma in the United States is 0.075 - 0.01 per 100, 000. The prevalence rates from Southeast Asia are 1.5 - 2.5 times higher. The 5-year overall mortality rate, after the exclusion of placental site trophoblastic tumors and epithelioid trophoblastic tumors, is 2%. High-risk patients have a 5-year mortality rate of 12%. Patients with an International Federation of Gynecology and Obstetrics (FIGO) score of ≥13 have a 5-year mortality rate of 38.4%. The incidence of gestational trophoblastic neoplasia is higher in the extremes of reproductive ages. In Southasia, the incidence rates are double for Eurasians as compared to people of Chinese, Malaysian, or Indian origin. African Americans have a decreased incidence rate as compared to caucasians. The incidence is also higher in the Latin American population. Europe, North America, Australia, some areas of Latin America, and the Middle East have low incidence ratios.Symptoms of choriocarcinoma include vaginal bleeding, passing of tissue resembling a “bunch of grapes” from the vagina, and abdominal distention. Elevated serum human chorionic gonadotropin suggests diagnostic of choriocarcinoma.Chest radiography (CXR) may be helpful in the diagnosis of pulmonary metastasis of choriocarcinoma. The characteristic findings of pulmonary metastasis are peripheral, rounded nodules of variable size scattered throughout both lungs.CT scan may be performed to detect metastasis of choriocarcinoma to lung, brain, and liver.MRI may be performed to detect metastasis of choriocarcinoma to brain and spinal cord.

Historical Perspective

In 6th century, Aetius of Amida, a physician at Justinian's court came up with the term 'hydatid'. Next mention of 'mole' is from 1276 when Margaret, Countess of Henneberg, delivered approximately 300 babies on Good Friday (the Friday before Easter Sunday). In 1827, Marie Anne Victoire Boivin, a Parisian midwife, proposed her findings of this condition in 'Nouvelles Recherches de la Mole Visiculaire' (News Searches of the Vesicular Mole). In 1840, William Wilton reported a case of invasive mole that was complicated by uterine perforation and fatal internal hemorrhage. In 1867, Richard von Volkmann, a German surgeon, also described a lesion resembling an invasive mole. In 1877, Hans Chiari, an Austrian pathologist, reported three cases of choriocarcinoma. He recognized the tumors as epithelial. In 1888, Max Sanger, a German obstetrician, proposed his theory that these tumors were actually sarcomas('deciduoma malignum'). In 1890, Pfeiffer, a student of Hans Chiari, re-examined Chiari's cases and added a fourth case. He named them all 'deciduoma malignum'. In 1891, Pestalozza from Italy, reported three cases of a malignantuterine tumor associated with pregnancy. He described these cases as 'sarcoma hemorrhagicum sen infectiosum'.

Classification

Gestational trophoblastic neoplasia may be classified according to histology into four subtypes: invasive mole, choriocarcinoma, placental-site trophoblastictumor, and epithelioid trophoblastic tumor.

Pathophysiology

Pregnancy occurs when an egg, which is released from the ovary during ovulation, is fertilized by a sperm. Human pregnancy takes approximately 40 weeks. Gestational trophoblastic neoplasia arises from the trophoblastic tissue, which provides nutrients to the embryo and develops into a large part of the placenta. Invasive mole is basically a benign tumor which arises from the invasion of the myometrium of a hydatidiform mole. Choriocarcinoma is a malignant tumor of the trophoblastic epithelium. Placental-site trophoblastic tumor (PSTT), a rare tumor, arises from the implantation site of placenta. Epithelioid trophoblastic tumor (ETT) is basically a rare variant of placental-site trophoblastic tumor (PSTT) which arises from the malignant transformation of chorionic-type intermediate trophoblastic cells. Invasive mole is usually diploid but can also be aneuploid in karyotype. Choriocarcinoma has an aneuploidkaryotype and majority of the cases have a Y chromosome.

Causes

Complete hydatidiform mole arises when an ovum without maternal chromosomes is fertilized by one sperm which duplicates its DNA, resulting in a 46XX androgenetic karyotype. Partial hydatidiform moles are almost always triploid, resulting from the fertilization of a healthy ovum by two sperms. Abnormal trophoblastic population undergoing hyperplasia and anaplasia can give rise to choriocarcinoma. Gestational type choriocarcinoma arises following a hydatidiform mole, normal pregnancy, or most commonly, abortion. Non-gestational type choriocarcinoma arises from pluripotent germ cells. Placental-site trophoblastic tumor (PSTT) arises from the placental implantation site when the trophoblastic cells infiltrate the myometrium. Epithelioid trophoblastic tumor (ETT) arises from the intermediate trophoblastic cells of chorion.

Differential Diagnosis

Gestational trophoblastic neoplasia (invasive mole, choriocarcinoma, placental-site trophoblastic tumor [PSTT] and epitheloid trophoblastic tumor [ETT]) should be differentiated from other conditions presenting with similar symptoms and signs such as increase in uterine size, vaginal bleeding and amenorrhea. The differentials include molar pregnancy (complete and partial moles), ovarian tumors, spontaneous abortion, ectopic pregnancy and normal term pregnancy.

Epidemiology and Demographics

The reported incidence of choriocarcinoma in the United States is 2 to 7 per 100,000 pregnancies. The U.S. age-standardized (1960 World Population Standard) incidence rate of choriocarcinoma is approximately 0.18/100,000 women between the ages of 15 - 49 years. The prevalence of choriocarcinoma in the United States is 0.075 - 0.01 per 100, 000. The prevalence rates from Southeast Asia are 1.5 - 2.5 times higher. The 5-year overall mortality rate, after the exclusion of placental site trophoblastic tumors and epithelioid trophoblastic tumors, is 2%. High-risk patients have a 5-year mortality rate of 12%. Patients with an International Federation of Gynecology and Obstetrics (FIGO) score of ≥13 have a 5-year mortality rate of 38.4%. The incidence of gestational trophoblastic neoplasia is higher in the extremes of reproductive ages. In Southasia, the incidence rates are double for Eurasians as compared to people of Chinese, Malaysian, or Indian origin. African Americans have a decreased incidence rate as compared to caucasians. The incidence is also higher in the Latin American population. Europe, North America, Australia, some areas of Latin America, and the Middle East have low incidence ratios.

Risk Factors

Common risk factors in the development choriocarcinoma include extremes of parental reproductive age, history of gestational trophoblastic disease, reproductive factors such as parity and abortion, parental blood group, oral contraceptive use, genetic factors, and environmental and lifestyle factors.

Natural History, Complications and Prognosis

Patients with gestational trophoblastic neoplasia (GTN) initially present with abnormal vaginal bleeding. The vaginal bleeding can also be associated with elevation of βhCG. In rare instances, patients can also initially present with symptoms related to distant metastasis to different organs. Patients can experience nausea and vomiting similar to the course of normal pregnancy. If left untreated, patients with gestational trophoblastic neoplasia (GTN) may develop metastatic lesions in different organs and can result in death. Complications of gestational trophoblastic neoplasia (GTN) include disseminated disease, hemorrhagic shock, massive hemoptysis, Acute abdomen, ovarian hyperstimulation, renal hemorrhage, severe hyperthyroidism, cardiothyreosis, and death. Poor prognostic factors include age > 35 years, interval since the last pregnancy of over 2 years, deep myometrial invasion, advanced stage, maximum βhCG level > 1000 mIU/ml, extensive coagulative necrosis, high mitotic rate, and presence of cells with clear cytoplasm.

Diagnosis

Staging

According to the Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) cancer staging system, there are 4 stages of choriocarcinoma.

History and Symptoms

Symptoms of choriocarcinoma include vaginal bleeding, passing of tissue resembling a “bunch of grapes” from the vagina, and abdominal distention.

Physical Examination

Common physical examination findings of choriocarcinoma include abdominal distension, pelvic/adnexal mass, and blood in vaginal discharge.

Laboratory Findings

Elevated serum human chorionic gonadotropin is diagnostic of choriocarcinoma.

Chest Xray

Chest radiography (CXR) may be helpful in the diagnosis of pulmonary metastasis of choriocarcinoma. The characteristic findings of pulmonary metastasis are peripheral, rounded nodules of variable size scattered throughout both lungs.

CT

CT scan may be performed to detect metastasis of choriocarcinoma to lung, brain, and liver.

MRI

MRI may be performed to detect metastasis of choriocarcinoma to brain and spinal cord.

Ultrasound

Ultrasound may be performed to detect metastasis of choriocarcinoma to the pelvis and abdomen.

Treatment

Medical therapy

The mainstay of therapy for choriocarcinoma is chemotherapy.

Surgery

Surgery is the mainstay of treatment for choriocarcinoma.

Prevention

Primary prevention

There are no established measures for primary prevention of gestational trophoblastic neoplasia.

Secondary prevention

Careful monitoring after the removal of hydatidiform mole or termination of pregnancy can lead to early diagnosis of a choriocarcinoma, which improves outcome.

References