Trophoblastic tumors

　　The cause of the occurrence of trophoblastic tumors is still unknown. Although many hypotheses have been put forward, they can only explain part of the phenomena. The etiology can be roughly summarized into the following aspects:

　　1. Malnutrition Theory: Lack of folic acid in experimental animals can lead to embryonic death, and it is speculated that maternal deficiency of folic acid may be related to the occurrence of trophoblastic tumors. Especially during the period of embryonic vascular formation (13-21 days after conception), if there is a lack of folic acid and histidine in nutrients, it will affect the synthesis of thymine, resulting in a lack of blood vessels in the placental villi and embryonic necrosis. The basic pathological changes of hydatidiform mole also conform to this point. From the geographical distribution of hydatidiform mole, hydatidiform mole and trophoblastic tumors are highly prevalent among residents who take rice and vegetables as their main food, due to the overcooking of food, which destroys and loses a large amount of protein, vitamins, and folic acid. Foreign scholars have also confirmed that the activity of folic acid in the serum of patients with trophoblastic diseases is very low. There are also reports that the concentrations of urea and creatinine in the plasma of patients with hydatidiform mole are significantly higher than those in the control group, and the plasma albumin and total protein are significantly lower, which is believed to be caused by improper diet and abnormal catabolism. However, this theory cannot explain why one fetus in a twin pregnancy develops into a hydatidiform mole, while the other can still develop normally. There are no clinical controlled observations on the dietary causes of hydatidiform mole, and there is no exact data to confirm this. In recent years, research in the United States and Italy has shown that a lack of carotenoids is related to the occurrence of hydatidiform mole. Therefore, it is proposed that women in high-incidence areas of hydatidiform mole can prevent the occurrence of hydatidiform mole by adopting dietary supplements of carotenoids and vitamin A.

　　2. Theory of VirusThere are reports suggesting that hydatidiform mole is related to viral infection. In the 1950s, Ruyck reported the isolation of a filterable virus from hydatidiform mole and绒癌tissues, called '绒毛病毒', and believed that this virus is the cause of trophoblastic tumor. However, for more than 30 years, no one has confirmed the existence of this virus. In the 1960s, some authors found some inclusion bodies in the cytoplasm of trophoblastic tumor specimens by electron microscopy, similar to the viral particles seen in experimental leukemia, thus proposing the view that trophoblastic tumor is induced by filterable virus, but there are also objections.

　　3. Theory of Endocrine DisorderThe clinical data of Peking Union Medical College Hospital shows that the opportunity of trophoblastic tumor (disease) in women under 20 years old and over 40 years old after pregnancy is relatively high. The WHO comprehensive report shows that the incidence of hydatidiform mole in the 15-20 age group is higher than that in the 20-35 age group, and the risk of onset increases after 40 years old. The risk of hydatidiform mole after pregnancy at the age of 50 and above will be 200 times that of the 20-35 age group. During this period, the characteristics of incomplete or gradually declining ovarian function are present, so it is associated with whether the trophoblastic tumor is closely related to the ovarian endocrine function, and whether the ovarian dysfunction is related to the incomplete eggs produced. Animal experiments have shown that early pregnancy ovaries can lead to vesicular degeneration of the placenta, thus it is believed that estrogen deficiency may be one of the causes of hydatidiform mole. Clinically, women who stop taking oral contraceptives, if they become pregnant and have a miscarriage in a short period of time, often show vesicular degeneration of the villi, indicating that the degeneration of villi is related to the imbalance of ovarian endocrine.

　　4. Theory of Ovum DefectMore authors believe that the occurrence of hydatidiform mole is related to the abnormality of the ovum. As mentioned above, the incidence of hydatidiform mole is higher in women under 20 years old or over 40 years old. The natural abortion rate and neonatal malformation rate in this age group of women are also high, which may be related to the inherent defects of the ovum itself. Research data on birth defects in China also prove that the incidence of malformations in pregnant women under 20 years old or over 40 years old is high, which also supports the related factors of ovum defects. The abnormality or the ovum can implant, but the embryo part does not have enough vitality, while the trophoblast has excessive growth power, thus developing into hydatidiform mole.

　　5. Race Factor: Hydatidiform mole is more common in various Asian countries, especially in Southeast Asia. Some people believe that it may be related to race. However, the issue of race is related to factors such as environment, climate, diet, water source, infectious diseases, and animal vectors. The incidence of gestational trophoblastic disease in different races of women in Hawaii, including the East (including Japan, China, Philippines), accounts for 49% of the local population, but accounts for 72% of the number of cases of gestational trophoblastic tumors. While the white population, accounting for 30% of the population, accounts for 14% of the incidence. The Hawaiian population accounts for less than 20% of the population and 9% of the incidence.

　　6. Cell Genetic Abnormality Theory: A large amount of data has been accumulated in the cytogenetic study of hydatidiform mole, which is of great clinical and theoretical significance for exploring its occurrence. The research on chromatin and chromosomes has found that the majority of trophoblasts in hydatidiform mole are positive for sex chromatin. Sex chromatin appears in the trophoblasts of human embryos on the 11th day, and can exist throughout a person's life. It shows one of the two sex chromosomes in human female stromal cells, which can be stained during division and can be seen under a low-power microscope. In 1957, Park discovered that positive sex chromatin is dominant, and most hydatidiform moles show femininity. Later, many authors have successively confirmed that although the ratio of positive to negative is not the same, the positive sex chromatin is always dominant.

　　7. Immune Theory:For pregnant women, the placenta is a non-rejected allograft. Both the embryo and gestational trophoblastic tumors have some paternal components, so theoretically, growth within the mother's body, like allografts, may cause immune rejection in the mother. The reason why the embryo is not rejected is that the villi have a buffering substance on the outer layer, which can prevent the graft antigens from entering the mother's body, thus not causing a maternal lymphocyte reaction. It is known that the normal placenta has human lymphocyte antigens (HLA), that is, all the cells contained in the intact placenta may express HLA antigens. As for whether the trophoblasts express HLA, opinions are not consistent, and it is unknown which component of the fetal lymphocytes in the trophoblasts, villous stromal cells, or stromal vessels contains it. A few hydatidiform moles contain specific antibodies against paternal HLA antigens. Since the villi of hydatidiform mole lack stromal vessels, it can be excluded that fetal lymphocytes cause the mother to form anti-HLA antibodies, but the villous stroma can directly contact the mother's body through the destruction of placental integrity, and it is still possible to cause antibody production, so it cannot be concluded that it is the trophoblasts of the hydatidiform mole or the stromal cells that cause immune response in the mother.

　　It has been indicated that complete hydatidiform mole has HLA antigens, and the HLA analysis also supports the cytogenetic conclusion. Complete hydatidiform mole is caused by the fertilization of haploid sperm, not by the second meiotic division of diploid sperm with anomalies. The chromosome replication occurs after meiosis. This mechanism will inevitably lead to the dominance of 46XX hydatidiform mole, as YY sperm cannot survive and die during early division. Of course, complete hydatidiform moles caused by other reasons cannot be ruled out either.

　　滋养细胞肿瘤可能会并发难以控制的大出血。严重感染时可能引起腹膜炎或败血症。此病并发急性肺栓塞、大量小葡萄珠侵入肺动脉，可能导致病人迅速死亡。本病还可能并发急性肺源性右心衰竭。部分胎盘部位滋养细胞肿瘤可能合并肾病综合征、红细胞增多症、脾大或蜘蛛痣。

　　葡萄胎是一种良性的滋养细胞肿瘤，因此也称为良性葡萄胎（benign mole）。良性葡萄胎的症状通常与妊娠相似，包括闭经和妊娠反应。但妊娠反应通常比正常妊娠早且明显，闭经6至8周后即开始出现不规则阴道流血。最初出血量较少，呈暗红色，时出时止，逐渐增多，连续不断，因此患者常出现不同程度的贫血。当葡萄胎要自行排出时（通常在妊娠4个月左右），可能会发生大出血，处理不及时可能导致患者休克甚至死亡。在排出血液中，有时可见透明的葡萄样物质，如果发现则对诊断有很大帮助。

　　大约10%的患者除了妊娠剧吐外，还可能出现蛋白尿、水肿、高血压等妊娠期高血压疾病，甚至可能出现子痫症状，如抽搐和昏迷，也有可能发生心功能衰竭。由于正常妊娠很少在妊娠20周前出现妊娠期高血压疾病，如果出现应立即怀疑为葡萄胎。有时患者也可能出现心慌气短。过去认为是合并心脏病，近年来知道是由于HCG增加导致甲状腺功能亢进。在葡萄胎中，腹痛并不常见，即使有也属于急性腹痛，主要发生在初孕妇子宫异常增大者。但葡萄胎即将排出时，可能因为子宫收缩而有阵发性腹痛，此时常伴有出血增多现象。如果葡萄胎未排出时出现急性腹痛，应考虑并发症的发生。葡萄胎患者肺无明显转移，但有咯血，葡萄胎排出后咯血立即消失。

　　绒毛膜癌是一种高度恶性的滋养细胞肿瘤，包括妊娠性和非妊娠性绒癌。妊娠性绒癌的临床常见症状为葡萄胎、流产或足产后阴道持续不规则出血，出血量不定。有时也可能在正常月经后出现闭经，随后发生阴道出血。此时与一般流产极易混淆，有人甚至将闭经误认为一次流产，认为绒癌是继发于这次流产。如果绒癌未及时发现（早期），也可能合并再次妊娠，表现为妊娠期反复出血，因此可能误诊为先兆流产（早期妊娠）或前置胎盘（中晚期妊娠），出血量不定，但以反复大量出血为多。

　　非妊娠绒癌的临床表现和妊娠性绒癌则很不相同，妊娠性绒癌均发生于生育年龄妇女，并有既往妊娠史，而非妊娠绒癌则多见于青春期发育男女或儿童期，男性病人常可出现乳房肿大、睾丸肿胀(曲精细胞和睾丸间质细胞增生)。青春发育期女子可有性早熟和乳腺增殖现象，也由于非妊娠性绒癌常合并其他生殖细胞肿瘤，除了绒癌部分发生转移造成各种症状外，尚可因其他肿瘤的发展而产生更多的其他症状，因而临床表现也更为复杂。

　　滋养细胞肿瘤(疾病)至今由于真正的病因不清楚，故迄今尚无预防有效预防措施，需要注意如下几点。

　　1、实行计划生育

　　一般来说中国实行计划生育，控制人口增长，采取了一系列的避孕措施，积极开展优生优育工作，对减少和降低葡萄胎的发生及其恶变也起到积极作用。

　　2、预防性子宫切除

　　因为恶性滋养细胞肿瘤除局部浸润外，主要通过血行播散，所以对子宫切除方法也并不能完全防止恶变，国外也有报道采用剖宫或子宫切除以后恶变机会增多。1989年第四届世界滋养细胞疾病会议上菲律宾报告1619例葡萄胎，其中预防性子宫切除，化疗加子宫切除共404例，子宫标本病检为恶性及随访后恶变仅35例，恶变率占总数的2.2％，比1976～1982年报告的恶变率7％为低，认为采用上述两措施，可降低葡萄胎后滋养细胞肿瘤的发生率。

　　3、预防性化疗

　　预防性化疗药物均有一定毒性，需要住院进行，费用较大，为预防15％左右的病人发生恶变而对所有患葡萄胎者均进行化疗，需费很大力量，承担一定风险，是否合理值得慎重考虑，不宜将预防性化疗列为常规。根据北京协和医院的经验，只对一些恶变机会较大的病例进行预防性化疗，如年龄>40岁，吸宫前子宫大于停经月份，HCG值异常高者，葡萄胎排除后仍有症状，HCG一度下降又持续上升者或来自偏僻地区又无定期随访可能者，则可予考虑。目前多数均不主张对所有葡萄胎病人给予预防性化疗，而主张在HCG监护下，根据葡萄胎排出后的HCG水平，子宫的大小，有无黄素囊肿，病人的年龄等决定是否给予预防性化疗。

　　4、随访工作

　　预防葡萄胎恶变，目前的关键是做好随访工作。因为通过随访能对发生恶变的病例做到早期发现、早期诊断和早期治疗，仍可以做到减少恶变造成的危害性。

　　Trophoblastic tumors refer to tumors formed by the malignant transformation of trophoblasts in the embryo. The clinical examination of this disease is as follows.

　　1. Chorionic gonadotropin measurementChorionic gonadotropin (HCG) produced by trophoblasts is an ideal tumor marker for trophoblastic tumors and has special significance for the diagnosis and treatment of such tumors. In recent years, with the development of science and technology such as biochemistry, molecular biology, radioimmunoassay, radioimmunoreceptor assay, monoclonal antibody preparation, hormone immunofluorescence assay, and electron microscopy technology, there has been a further understanding of the secretion site, molecular structure, amino acid sequence, and biological and immunological functions of HCG. It is known that HCG is a protamine that is easily soluble and does not coagulate when heated. The alpha-subunit of HCG is the same as that of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Therefore, it can produce cross-reactivity, while the beta-subunit structure is unique to HCG. The content of HCG in blood, urine, and cerebrospinal fluid is related to the number and activity of trophoblasts in the body, so the determination of HCG content is helpful for the diagnosis and treatment of normal and abnormal pregnancy, and has greater application value in the diagnosis and treatment of trophoblastic tumors, and can be regarded as a specific tumor marker for trophoblastic tumors.

　　2. Detection of pregnancy-specific proteinsIn addition to HCG, trophoblastic tumors produce妊娠特异蛋白such as placental lactogen (HPL),妊娠特异糖蛋白(SP), placental protein 5 (PP5), and pregnancy-associated protein A (PAPPA).

　　3. Cytokine detectionCytokines are soluble small peptides and glycoproteins secreted by immune-competent cells and stromal cells, which constitute a complex network system for transmitting signals between cells. In addition to participating in necessary immune functions, they also act as autocrine and paracrine growth factors, playing an important role in the occurrence and growth of trophoblastic tumors.

　　4. Flow cytometry (FCM)Tumor tissue is made into a single-cell suspension, stained with DNA-specific fluorescent dyes, and the detection results are displayed using the principle that the fluorescence intensity is proportional to the DNA content. At least 1000 cells can be checked per second, and most solid tumor cell populations are diploid. When another G1 peak is present, it is aneuploid. The different degrees of aneuploidy are represented by DNA index (DI), with DI1 equivalent to diploid tumor, DI1.5 indicating trisomy, and a high DI indicating strong tumor proliferation.

　　5. Polymerase chain reaction (PCR) technologyThe British Fisher et al. reported that the DNA polymerase chain reaction (PCR) technique can correctly classify hydatidiform mole into partial, single sperm complete, and double sperm complete types by detecting DNA in the blood lymphocytes of couples and hydatidiform mole tissue.

　　6. Fluorescence in situ hybridization (FISH)The University of Pittsburgh, USA, has detected abnormal chromosomes 1, 7, 12, 13, and 21 in绒癌细胞株using the fluorescence in situ hybridization technique (FISH), and partial DNA amplification of chromosome 12.

　　7. Cytological Examination: Use gene microarray chip technology to screen expressed genes.

　　8. B-ultrasound Examination: The clinical application of ultrasonic examination shows that B-ultrasound can clearly display soft tissue images. Currently, the application of B-ultrasound in the diagnosis, treatment effect observation, and follow-up of trophoblastic tumors in China is very common. It can improve the early diagnosis rate when combined with HCG measurement.

　　9. X-ray Examination:X-ray examination is an important means in the diagnosis of trophoblastic tumors, mainly used for lung examination. X-ray diagnosis is also needed for other metastases such as uterus, bone, heart, gastrointestinal tract, and urinary system.

　　10. Laparoscopy: Laparoscopy can be used for the diagnosis and treatment of trophoblastic diseases and has unique features.

　　Patients with trophoblastic tumors should have a light diet. One of its therapeutic recipes is sea cucumber stewed with Chinese yam and American ginseng.

　　Sea Cucumber Stewed with Chinese Yam and American Ginseng

　　Herbal Formula and Dosage: Use 96 grams of sea cucumber, 10 grams of American ginseng (separately packaged, only cook for 15 minutes), 250 grams of pork backbone, 65 grams of Chinese yam, appropriate amount of salt and peanut oil. First, cut the sea cucumber into small pieces and put it in a large炖盅 with the chopped pork backbone, add Chinese yam, appropriate amount of water, and simmer for 1 hour over low heat. Then add slices of American ginseng, goji berries, sesame oil, and salt, and simmer for another 15 minutes. Drink the soup in portions and eat the sea cucumber.

　　Effectiveness: Prevent and treat cancer, tonify Qi and nourish blood.

　　Trophoblastic tumor refers to a tumor formed by the malignant transformation of the trophoblasts of the embryo. It was originally divided into two types, one benign called 'hydatid mole', and the other malignant called 'choriocarcinoma'. The specific treatment measures for this disease are as follows.

　　1. Treatment of Hydatid Mole

　　Although hydatid mole is benign, there is also a certain degree of risk if not handled properly. Once hydatid mole is diagnosed, it should be cleared promptly. Currently, the method of aspiration is used. Its advantages are short operation time, less bleeding, and less risk of surgical perforation, making it relatively safe.

　　2. Treatment of Malignant Trophoblastic Tumor

　　The harmfulness of invasive mole and choriocarcinoma is much greater than that of benign mole. Once diagnosed, timely treatment is required. In the past, the method of hysterectomy was adopted, with very poor results, especially for choriocarcinoma.