Введение
Злокачественная трофобластная опухоль, возникающая на фоне гестации
Gestational choriocarcinoma is a form of gestational trophoblastic neoplasia, which is a type of gestational trophoblastic disease (GTD), that can occur during pregnancy. It is a rare disease where the trophoblast, a layer of cells surrounding the blastocyst, undergoes abnormal developments, leading to trophoblastic tumors. The choriocarcinoma can metastasize to other organs, including the lungs, kidney, and liver. The amount and degree of choriocarcinoma spread to other parts of the body can vary greatly from person to person. Gestational choriocarcinoma can happen during and after any type of pregnancy event, though risk of the disease is higher in and after complete or partial molar pregnancies. Approximately 50% of those with gestational choriocarcinoma have experienced molar pregnancy, approximately 25% developed the disease after a regular, term pregnancy, and other situations have included history of ectopic pregnancy, where the pregnancy does not occur in the uterus. Statistics from clinical cases have shown that GC is associated with any pregnancy events, with 50% of GC arise from hydatidiform moles, 25% from gestation, and 25% from abortion or tubal pregnancy. Prior history of complete hydatidiform mole. This is another well established risk factor for GC. It has been showed that the risk of having GC after a complete hydatidiform mole is significantly higher than after a live birth. Each of them possesses distinct specialized functions to support a developing embryo. Cytotrophoblasts are the germinating cells that forms the chorion villi and can be differentiated into syncytiotrophoblasts which produce hCG and can intrude to the inner muscle layer of the uterus to help embed the developing embryo, and intermediate trophoblasts which spread throughout the chorion villi to support maternal fetal circulation. Common pathological features of GC include abnormal trophoblastic enlargement, loss of trophoblastic specialized features and functions, absence of villi in the placenta, abnormal bleeding, and necrosis. Many efforts have been made to try to understand the mechanism of how non malignant mole could become invasive. It is suspected that activation of certain oncogenes (such as up regulations of MDM2, c ERB2, and BLC2) and inactivation of tumor suppressor genes (such as up regulations of p53, p21) were involved in the processes of genetic changes in this malignant transformation. Long non coding RNAs are groups of RNAs that do not code for protein expression and are usually over 200 nucleotides long; they are increasingly recognized to have essential role in many aspects of cellular function, like transcriptional regulation, sub cellular protein localization, and epigenetic remodeling. Often, diagnosis is presumptive. It is based on clinical findings and the identification of a malignant trophoblast. One prevalent symptom is vaginal bleeding after a pregnancy, abortion, or hydatidiform mole. In the presence of choriocarcinoma, a pregnancy test will be positive even if there is no embryo/fetus. Individuals presented with the disease are mostly in their reproductive years. Based on the International Federation of Gynecology and Obstetrics (FIGO)'s updated guidelines on gestational trophoblastic disease management, the diagnostic criteria of a post gestational trophoblastic neoplasia (GTN) is as follows:
Over a period of 3 weeks or longer (day 1, 7, 14, 21), there are 4 or more plateaued hCG levels. Over a period of 2 weeks or longer (day 1, 7, 14), there are 3 consecutive weekly measurements of rising hCG levels. A histological diagnosis of choriocarcinoma. There are currently different guidelines available in terms of diagnosing and recommending treatment options for gestational trophoblastic neoplasia (GTN). The 4 guidelines identified are: the Royal College of Obstetricians and Gynecologists (RCOG), the International Federation of Gynecology and Obstetrics (FIGO), the European Society for Medical Oncology (ESMO), and the Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG). The differences in GTN diagnosis between the guidelines are as follows:
+Comparison chart of available guidelines on gestational trophoblastic neoplasia (GTN) diagnosis criteriaRCOGESMOFIGORANZCOGClinical presentationxxFIGO Criteria (*see above)xxxxUrine hCG levelxPost molar hCG levelxx
To differentiate gestational choriocarcinoma from other tumors such as lung or brain cancers, a genetic test is usually completed on top of a pathological diagnosis. DNA genotyping is a powerful tool that helps with the differentiation. The technique can accurately determine the time that it takes to develop the observed tumor and the type of index gestation, which includes term pregnancy, molar gestation, or non molar abortion.
Гестационная хориокарцинома является формой гестационной трофобластной неоплазии, которая, в свою очередь, представляет собой тип гестационного трофобластного заболевания (ГТЗ), способного развиваться во время беременности. Это редкое заболевание, при котором трофобласт – слой клеток, окружающий бластоцисту – претерпевает аномальное развитие, приводящее к образованию трофобластных опухолей. Хориокарцинома может метастазировать в другие органы, включая легкие, почки и печень. Степень и объем распространения хориокарциномы по организму могут значительно варьировать у разных пациентов. Гестационная хориокарцинома может возникать во время и после любого типа беременности, однако риск заболевания выше при полной или частичной молярной беременности. Примерно у 50% пациенток с гестационной хориокарциномой в анамнезе была молярная беременность, примерно у 25% заболевание развилось после нормальной, доношенной беременности, а в других случаях отмечалась история внематочной беременности, когда беременность не развивается в матке. Статистические данные клинических случаев показывают, что ГК связана с любыми событиями, связанными с беременностью: в 50% случаев ГК развивается из гидатидиформных родин, в 25% – после беременности, и в 25% – после аборта или трубной беременности. Наличие в анамнезе полной гидатидиформной родинки является еще одним установленным фактором риска развития ГК. Показано, что риск развития ГК после полной гидатидиформной родинки значительно выше, чем после рождения живого ребенка. Каждый из этих типов клеток обладает уникальными специализированными функциями, необходимыми для поддержания развивающегося эмбриона. Цитотрофобласты – это пролиферирующие клетки, формирующие ворсины хориона, которые могут дифференцироваться в синцитиотрофобласты, продуцирующие ХГЧ и проникающие во внутренний мышечный слой матки для имплантации развивающегося эмбриона, а также в промежуточные трофобласты, распространяющиеся по ворсинам хориона для обеспечения материно-плодного кровообращения. Общие патологические признаки ГК включают аномальное увеличение трофобласта, потерю специализированных признаков и функций трофобласта, отсутствие ворсин в плаценте, аномальные кровотечения и некроз. Предпринято множество усилий для понимания механизмов, посредством которых незлокачественная моль может стать инвазивной. Предполагается, что в процессах генетических изменений, приводящих к злокачественной трансформации, участвуют активация определенных онкогенов (например, MDM2, c-ERB2 и BCL2) и инактивация генов-супрессоров опухолей (например, p53, p21). Длинные некодирующие РНК – это группы РНК, которые не кодируют белки и обычно имеют длину более 200 нуклеотидов; все чаще признается их важная роль во многих аспектах клеточной функции, таких как регуляция транскрипции, субклеточная локализация белков и эпигенетическое ремоделирование. Часто диагноз является предположительным и основывается на клинических данных и выявлении злокачественного трофобласта. Распространенным симптомом является вагинальное кровотечение после беременности, аборта или гидатидиформной родинки. При наличии хориокарциномы тест на беременность будет положительным, даже при отсутствии эмбриона/плода. Большинство пациенток с этим заболеванием находятся в репродуктивном возрасте. Согласно обновленным рекомендациям Международной федерации гинекологии и акушерства (FIGO) по ведению гестационного трофобластного заболевания, критерии диагностики постгестационной трофобластной неоплазии (ГТН) следующие:
Gestational choriocarcinoma is a form of gestational trophoblastic neoplasia, which is a type of gestational trophoblastic disease (GTD), that can occur during pregnancy. It is a rare disease where the trophoblast, a layer of cells surrounding the blastocyst, undergoes abnormal developments, leading to trophoblastic tumors. The choriocarcinoma can metastasize to other organs, including the lungs, kidney, and liver. The amount and degree of choriocarcinoma spread to other parts of the body can vary greatly from person to person. Gestational choriocarcinoma can happen during and after any type of pregnancy event, though risk of the disease is higher in and after complete or partial molar pregnancies. Approximately 50% of those with gestational choriocarcinoma have experienced molar pregnancy, approximately 25% developed the disease after a regular, term pregnancy, and other situations have included history of ectopic pregnancy, where the pregnancy does not occur in the uterus. Statistics from clinical cases have shown that GC is associated with any pregnancy events, with 50% of GC arise from hydatidiform moles, 25% from gestation, and 25% from abortion or tubal pregnancy. Prior history of complete hydatidiform mole. This is another well established risk factor for GC. It has been showed that the risk of having GC after a complete hydatidiform mole is significantly higher than after a live birth. Each of them possesses distinct specialized functions to support a developing embryo. Cytotrophoblasts are the germinating cells that forms the chorion villi and can be differentiated into syncytiotrophoblasts which produce hCG and can intrude to the inner muscle layer of the uterus to help embed the developing embryo, and intermediate trophoblasts which spread throughout the chorion villi to support maternal fetal circulation. Common pathological features of GC include abnormal trophoblastic enlargement, loss of trophoblastic specialized features and functions, absence of villi in the placenta, abnormal bleeding, and necrosis. Many efforts have been made to try to understand the mechanism of how non malignant mole could become invasive. It is suspected that activation of certain oncogenes (such as up regulations of MDM2, c ERB2, and BLC2) and inactivation of tumor suppressor genes (such as up regulations of p53, p21) were involved in the processes of genetic changes in this malignant transformation. Long non coding RNAs are groups of RNAs that do not code for protein expression and are usually over 200 nucleotides long; they are increasingly recognized to have essential role in many aspects of cellular function, like transcriptional regulation, sub cellular protein localization, and epigenetic remodeling. Often, diagnosis is presumptive. It is based on clinical findings and the identification of a malignant trophoblast. One prevalent symptom is vaginal bleeding after a pregnancy, abortion, or hydatidiform mole. In the presence of choriocarcinoma, a pregnancy test will be positive even if there is no embryo/fetus. Individuals presented with the disease are mostly in their reproductive years. Based on the International Federation of Gynecology and Obstetrics (FIGO)'s updated guidelines on gestational trophoblastic disease management, the diagnostic criteria of a post gestational trophoblastic neoplasia (GTN) is as follows:
Over a period of 3 weeks or longer (day 1, 7, 14, 21), there are 4 or more plateaued hCG levels. Over a period of 2 weeks or longer (day 1, 7, 14), there are 3 consecutive weekly measurements of rising hCG levels. A histological diagnosis of choriocarcinoma. There are currently different guidelines available in terms of diagnosing and recommending treatment options for gestational trophoblastic neoplasia (GTN). The 4 guidelines identified are: the Royal College of Obstetricians and Gynecologists (RCOG), the International Federation of Gynecology and Obstetrics (FIGO), the European Society for Medical Oncology (ESMO), and the Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG). The differences in GTN diagnosis between the guidelines are as follows:
+Comparison chart of available guidelines on gestational trophoblastic neoplasia (GTN) diagnosis criteriaRCOGESMOFIGORANZCOGClinical presentationxxFIGO Criteria (*see above)xxxxUrine hCG levelxPost molar hCG levelxx
To differentiate gestational choriocarcinoma from other tumors such as lung or brain cancers, a genetic test is usually completed on top of a pathological diagnosis. DNA genotyping is a powerful tool that helps with the differentiation. The technique can accurately determine the time that it takes to develop the observed tumor and the type of index gestation, which includes term pregnancy, molar gestation, or non molar abortion.
В течение 3 недель или более (дни 1, 7, 14, 21) наблюдается 4 или более плато уровня ХГЧ. В течение 2 недель или более (дни 1, 7, 14) регистрируются 3 последовательных еженедельных измерения повышающегося уровня ХГЧ. Гистологический диагноз хориокарциномы. В настоящее время существуют различные рекомендации по диагностике и выбору тактики лечения гестационной трофобластной неоплазии (ГТН). Выделяют четыре основных руководства: Королевский колледж акушеров и гинекологов (RCOG), Международная федерация гинекологии и акушерства (FIGO), Европейское общество медицинской онкологии (ESMO) и Королевский австралийский и новозеландский колледж акушеров и гинекологов (RANZCOG). Различия в диагностике ГТН между этими руководствами следующие:
+Сравнительная таблица критериев диагностики гестационной трофобластной неоплазии (ГТН) в различных руководствах RCOGESMOFIGORANZCOGКлиническая картинаxxКритерии FIGO (*см. выше)xxxxУровень ХГЧ в мочеxУровень ХГЧ после молярной беременностиxx
Gestational choriocarcinoma is a form of gestational trophoblastic neoplasia, which is a type of gestational trophoblastic disease (GTD), that can occur during pregnancy. It is a rare disease where the trophoblast, a layer of cells surrounding the blastocyst, undergoes abnormal developments, leading to trophoblastic tumors. The choriocarcinoma can metastasize to other organs, including the lungs, kidney, and liver. The amount and degree of choriocarcinoma spread to other parts of the body can vary greatly from person to person. Gestational choriocarcinoma can happen during and after any type of pregnancy event, though risk of the disease is higher in and after complete or partial molar pregnancies. Approximately 50% of those with gestational choriocarcinoma have experienced molar pregnancy, approximately 25% developed the disease after a regular, term pregnancy, and other situations have included history of ectopic pregnancy, where the pregnancy does not occur in the uterus. Statistics from clinical cases have shown that GC is associated with any pregnancy events, with 50% of GC arise from hydatidiform moles, 25% from gestation, and 25% from abortion or tubal pregnancy. Prior history of complete hydatidiform mole. This is another well established risk factor for GC. It has been showed that the risk of having GC after a complete hydatidiform mole is significantly higher than after a live birth. Each of them possesses distinct specialized functions to support a developing embryo. Cytotrophoblasts are the germinating cells that forms the chorion villi and can be differentiated into syncytiotrophoblasts which produce hCG and can intrude to the inner muscle layer of the uterus to help embed the developing embryo, and intermediate trophoblasts which spread throughout the chorion villi to support maternal fetal circulation. Common pathological features of GC include abnormal trophoblastic enlargement, loss of trophoblastic specialized features and functions, absence of villi in the placenta, abnormal bleeding, and necrosis. Many efforts have been made to try to understand the mechanism of how non malignant mole could become invasive. It is suspected that activation of certain oncogenes (such as up regulations of MDM2, c ERB2, and BLC2) and inactivation of tumor suppressor genes (such as up regulations of p53, p21) were involved in the processes of genetic changes in this malignant transformation. Long non coding RNAs are groups of RNAs that do not code for protein expression and are usually over 200 nucleotides long; they are increasingly recognized to have essential role in many aspects of cellular function, like transcriptional regulation, sub cellular protein localization, and epigenetic remodeling. Often, diagnosis is presumptive. It is based on clinical findings and the identification of a malignant trophoblast. One prevalent symptom is vaginal bleeding after a pregnancy, abortion, or hydatidiform mole. In the presence of choriocarcinoma, a pregnancy test will be positive even if there is no embryo/fetus. Individuals presented with the disease are mostly in their reproductive years. Based on the International Federation of Gynecology and Obstetrics (FIGO)'s updated guidelines on gestational trophoblastic disease management, the diagnostic criteria of a post gestational trophoblastic neoplasia (GTN) is as follows:
Over a period of 3 weeks or longer (day 1, 7, 14, 21), there are 4 or more plateaued hCG levels. Over a period of 2 weeks or longer (day 1, 7, 14), there are 3 consecutive weekly measurements of rising hCG levels. A histological diagnosis of choriocarcinoma. There are currently different guidelines available in terms of diagnosing and recommending treatment options for gestational trophoblastic neoplasia (GTN). The 4 guidelines identified are: the Royal College of Obstetricians and Gynecologists (RCOG), the International Federation of Gynecology and Obstetrics (FIGO), the European Society for Medical Oncology (ESMO), and the Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG). The differences in GTN diagnosis between the guidelines are as follows:
+Comparison chart of available guidelines on gestational trophoblastic neoplasia (GTN) diagnosis criteriaRCOGESMOFIGORANZCOGClinical presentationxxFIGO Criteria (*see above)xxxxUrine hCG levelxPost molar hCG levelxx
To differentiate gestational choriocarcinoma from other tumors such as lung or brain cancers, a genetic test is usually completed on top of a pathological diagnosis. DNA genotyping is a powerful tool that helps with the differentiation. The technique can accurately determine the time that it takes to develop the observed tumor and the type of index gestation, which includes term pregnancy, molar gestation, or non molar abortion.
Для дифференциальной диагностики гестационной хориокарциномы с другими опухолями, такими как рак легких или головного мозга, обычно проводится генетическое тестирование в дополнение к патологоанатомическому диагнозу. Генотипирование ДНК является мощным инструментом, который помогает в дифференциальной диагностике. Эта методика позволяет точно определить время развития наблюдаемой опухоли и тип исходной беременности, включая доношенную беременность, молярную беременность или аборт.
Gestational choriocarcinoma is a form of gestational trophoblastic neoplasia, which is a type of gestational trophoblastic disease (GTD), that can occur during pregnancy. It is a rare disease where the trophoblast, a layer of cells surrounding the blastocyst, undergoes abnormal developments, leading to trophoblastic tumors. The choriocarcinoma can metastasize to other organs, including the lungs, kidney, and liver. The amount and degree of choriocarcinoma spread to other parts of the body can vary greatly from person to person. Gestational choriocarcinoma can happen during and after any type of pregnancy event, though risk of the disease is higher in and after complete or partial molar pregnancies. Approximately 50% of those with gestational choriocarcinoma have experienced molar pregnancy, approximately 25% developed the disease after a regular, term pregnancy, and other situations have included history of ectopic pregnancy, where the pregnancy does not occur in the uterus. Statistics from clinical cases have shown that GC is associated with any pregnancy events, with 50% of GC arise from hydatidiform moles, 25% from gestation, and 25% from abortion or tubal pregnancy. Prior history of complete hydatidiform mole. This is another well established risk factor for GC. It has been showed that the risk of having GC after a complete hydatidiform mole is significantly higher than after a live birth. Each of them possesses distinct specialized functions to support a developing embryo. Cytotrophoblasts are the germinating cells that forms the chorion villi and can be differentiated into syncytiotrophoblasts which produce hCG and can intrude to the inner muscle layer of the uterus to help embed the developing embryo, and intermediate trophoblasts which spread throughout the chorion villi to support maternal fetal circulation. Common pathological features of GC include abnormal trophoblastic enlargement, loss of trophoblastic specialized features and functions, absence of villi in the placenta, abnormal bleeding, and necrosis. Many efforts have been made to try to understand the mechanism of how non malignant mole could become invasive. It is suspected that activation of certain oncogenes (such as up regulations of MDM2, c ERB2, and BLC2) and inactivation of tumor suppressor genes (such as up regulations of p53, p21) were involved in the processes of genetic changes in this malignant transformation. Long non coding RNAs are groups of RNAs that do not code for protein expression and are usually over 200 nucleotides long; they are increasingly recognized to have essential role in many aspects of cellular function, like transcriptional regulation, sub cellular protein localization, and epigenetic remodeling. Often, diagnosis is presumptive. It is based on clinical findings and the identification of a malignant trophoblast. One prevalent symptom is vaginal bleeding after a pregnancy, abortion, or hydatidiform mole. In the presence of choriocarcinoma, a pregnancy test will be positive even if there is no embryo/fetus. Individuals presented with the disease are mostly in their reproductive years. Based on the International Federation of Gynecology and Obstetrics (FIGO)'s updated guidelines on gestational trophoblastic disease management, the diagnostic criteria of a post gestational trophoblastic neoplasia (GTN) is as follows:
Over a period of 3 weeks or longer (day 1, 7, 14, 21), there are 4 or more plateaued hCG levels. Over a period of 2 weeks or longer (day 1, 7, 14), there are 3 consecutive weekly measurements of rising hCG levels. A histological diagnosis of choriocarcinoma. There are currently different guidelines available in terms of diagnosing and recommending treatment options for gestational trophoblastic neoplasia (GTN). The 4 guidelines identified are: the Royal College of Obstetricians and Gynecologists (RCOG), the International Federation of Gynecology and Obstetrics (FIGO), the European Society for Medical Oncology (ESMO), and the Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG). The differences in GTN diagnosis between the guidelines are as follows:
+Comparison chart of available guidelines on gestational trophoblastic neoplasia (GTN) diagnosis criteriaRCOGESMOFIGORANZCOGClinical presentationxxFIGO Criteria (*see above)xxxxUrine hCG levelxPost molar hCG levelxx
To differentiate gestational choriocarcinoma from other tumors such as lung or brain cancers, a genetic test is usually completed on top of a pathological diagnosis. DNA genotyping is a powerful tool that helps with the differentiation. The technique can accurately determine the time that it takes to develop the observed tumor and the type of index gestation, which includes term pregnancy, molar gestation, or non molar abortion.
Лечение
Из-за высокой чувствительности хориокарциномы к химиотерапии, она является препаратом первой линии для лечения этого заболевания. Курс лечения определяется системой подсчета баллов FIGO для ГТН, которая учитывает различные прогностические факторы и классифицирует пациентов на группы низкого риска (с баллом от 0 до 6) и высокого риска (с баллом 7 и выше). Лечение включает комбинацию препаратов на основе платины и этопозида с другими химиотерапевтическими средствами, такими как метотрексат и актиномицин D (EMA EP), блеомицин (BEP) или ифосфамид (VIP, ICE). В таких случаях пациентам обычно назначают более интенсивный режим медикаментозной терапии, чем первоначальный.
Прогноз
Выживаемость после лечения химиотерапией составляет приблизительно не менее 90%. Если гестационная хориокарцинома распространилась на печень, выживаемость может быть ниже. Общая выживаемость также выше, когда лечение гестационной хориокарциномы проводится в медицинском учреждении, где врачи хорошо знакомы с этим заболеванием. Ранняя диагностика и своевременное лечение могут повысить шансы на сохранение репродуктивного потенциала у женщин, планирующих беременность. Возвращение уровня хорионического гонадотропина человека к нормальным значениям снижает риск рецидива гестационной хориокарциномы. Эти уровни можно контролировать ежемесячно в рамках последующего наблюдения. После химиотерапии пациентам следует подождать не менее одного года, прежде чем планировать беременность, чтобы минимизировать риск выкидыша.