Última actualización:
July 12, 2019
Años publicados: 2019
NORD gratefully acknowledges Xenia Parisi, MD, Resident Physician, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, and Enrique Hernandez, MD, Abraham Roth Professor and Chair, Obstetrics, Gynecology and Reproductive Sciences; Professor, Pathology and Laboratory Medicine, Temple University, Lewis Katz School of Medicine, for the preparation of this report.
Summary
The gestational trophoblastic diseases (GTDs) are a complex family of disorders. The term GTD is a general one, used to describe any of the group of diagnoses that behave out of character from what is expected of gestational trophoblastic tissue. The term GTD refers to both benign and malignant conditions. Gestational trophoblastic neoplasia (GTN) refers more specifically to malignant disease.
GTDs all arise from trophoblast cells. Trophoblasts are the population of cells responsi-ble for the formation of the placenta, a temporary but essential organ responsible for both the delivery of nutrients to and removal of waste from the growing fetus. It is important to note that GTDs can arise in the context of both normal pregnancy or ‘molar pregnancy’. A molar pregnancy is one in which an ovum or sperm combine to form a genetically non-viable zygote (single-celled precursor to the fetus and placenta). In this discussion, molar pregnancy will be described in detail as it serves as the precursor to the majority of GTDs that develop.
The products of conception in a molar pregnancy (the non-viable embryo and placental tissue) are described as a hydatiform mole. Hydatiform moles can be farther described as being ‘complete’ or ‘partial’. Hydatiform moles are distinct according to their several characteristics. They differ in their genetics, content of recognizable fetal components, propensity for co-morbid features, and propensity to progress to malignant disease. Malignant GTNs known to arise from hydatiform moles include the ‘invasive mole’ and choriocarcinoma. Two additional entities that arise from trophoblastic cells but which arise independently from molar pregnancy include the placental site trophoblastic tumors and epithelioid trophoblastic tumors. All of these entities are discussed in detail below. Finally, there are a series of trophoblastic cell deriveatives that will also be described, but only in brief, as their significance to patient care is unclear. This includes the benign placental site nodule and exaggerated placental site.
Introduction
Hydatiform Moles
A molar pregnancy describes the fertilization event of a genetically non-viable ovum by sperm. The normal ovum and sperm both carry one-half of the genetic information required for a normal conception. Their fusion forms the zygote. The normal zygote is the single resultant cell that carries the full set of genetic material required for the development of a fetus. The DNA that the ovum and sperm contribute are equal in content but not function. The healthy zygote requires one half of its DNA to be from the ovum and the sperm. A zygote is non-viable in the case where there is, for example, a duplication of one half set. When there is an abnormal genetic contribution from either the ovum or the sperm, a hydatiform mole has formed. The hydatiform mole will mimic the developmental stages of a normal pregnancy. It will implant into the uterine cavity and begin to grow. The woman’s body will feel as she would in a normal pregnancy. The discussion on differentiating between a normal and a molar pregnancy is discussed in subsequent sections below.
An important distinction to be made about the hydatiform moles is that their growth is contained within the uterine cavity. The benign hydatiform mole carries a risk to develop into malignant disease but is not in of itself malignant. The risk for the formation of malignancy is related to the type of hydatiform mole, whether it is partial or complete. The differences between a complete and partial hydatiform mole, are based on their genetic make-up. The genetic make-up of the zygote at the time of fertilization depends on the genetics of the ovum and sperm involved.
The cells of the human body typically carry a ’diploid’ genotype of 46 chromosomes, half from the individual’s mother and half from their father. The normal set of chromosomes is described as either a 46XX or 46XY genotype. A complete mole carries a 46XX or 46XY genotype and in this way is seemingly similar to the genotype that the normal zygote carries. However, despite the normal number of DNA copies, there exists severe epigenetic abnormalities given that the source of the DNA is not derived evenly from the maternal ovum and paternal sperm. Ninety percent of complete moles result from the duplication of a sperm that fertilizes an “empty” ovum, wherein maternal chro-mosomes are absent or inactive. The other ten percent of complete molar pregnancies are due to fertilization of an empty ovum by two different sperm. A partial mole generally carries ‘triploid’ genotype, described as XXX or XXY. The partial mole results from the fertilization of a normal ovum by two sperm.
Invasive Mole
The invasive mole is the malignant counterpart to the partial and complete hydatiform moles previously described. This entity is defined by the capacity to invade beyond the endometrial layer of the uterus where a normal pregnancy resides. Most often the invasive mole is seen extending into the vagina, vulva, or peritoneum (abdominal cavity). While this entity is locally destructive, it generally is limited to the region and does not carry the capacity to metastasize to distant locations such as the lungs. The invasive mole is to the hydatiform moles in terms of its histology, its appearance microscopically. Invasive moles demonstrate numerous minute projections along their surface. These projections are called villi. These villi are a structural analog to the normal placenta, where they serve as the contact surface between the maternal blood supply and that of the fetus. Other entities in the family of GTDs do not demonstrate these villi.
Choriocarcinoma
The normal placenta is formed by two cell populations, the cytotrophoblasts and syncytiotrophoblasts. The cytotrophoblasts form a layer over which syncytiotrophoblasts lay. Both two cell populations are essential in the process of implanting an embryo into the maternal uterine wall and in establishing the proper supply of blood and nutrients to the embryo. The invasion process however should be self-limiting to the endometrial layer of the uterus. When a mass of these cytotrophoblast and syncytiotrophoblast cell populations form a mass that retains the ability to invade surrounding tissue and metastasize to distant locations in the body, such as the lungs, they have formed a choriocarcinoma. On a cellular level, the choriocarcinoma also differs from the invasive mole due to the loss of previously described villi.
Rare Trophoblastic Tumor Variants
Placental site trophoblastic tumors (PSTT) and epithelioid trophoblastic tumors (ETT) are two additional entities that can arise from the aforementioned family of tropho-blastic cells. Specifically, these entities arise from ‘intermediate trophoblasts’. The in-termediate trophoblasts generally serve to anchor the placenta into the uterus. The intermediate trophoblasts can be described by location, which is associated with subtle differences in cell characteristics. The PSTT arises from intermediate trophoblasts at the villous (uterine) surface. The ETT arises from intermediate trophoblasts at the chorinic (fetal) surface.
Hydatiform Moles
While molar pregnancy represents a non-viable fertilization event, women may feel like they would in a normal, healthy pregnancy and come to the physician with a positive pregnancy test. Women may also present with complaints of passing heavy clots, even tissue from the vagina, mimicking a spontaneous abortion.
Overall, the presentation of a partial molar pregnancy is different from that of a complete molar pregnancy. A partial hydatiform mole usually presents with a small uterus compared to the expected size for a given gestational age. On ultrasound, there will be an abnormal placenta with large cystic spaces, said to resemble Swiss cheese, a small amount amniotic fluid, and potentially shocking and upsetting: fetal parts, even an entire fetus. In the case that there is a formed fetus it is important to note that it is usually very growth restricted and at high risk for birth defects.
A complete hydatiform mole usually presents with a large uterus compared to the expected size for a given gestational age. On ultrasound, there will be no embryo, fetus, or amniotic fluid. There will be an abnormal placenta with small cystic spaces, said to resemble a snowstorm. When a complete molar pregnancy presents with the passage of tissue from the vagina, the tissue is said to resemble large grape-like masses with a ‘prune-juice’ discharge. Finally, complete hydatiform moles are also associated with ovarian theca lutein cysts, pre-eclampsia, and hyperthyroidism. Theca lutein cysts form from overstimulation by circulating hormones produced by the complete hydatiform mole and can cause abdominal pains as they rupture or bleed. Pre-eclampsia is a disorder characterized by new onset hypertension. Patients might experience headaches over the back of their head that does not respond to medication, stars in their field of vision, pain in the right upper portion of the abdomen under the ribs, shortness of breath, and swelling in the face, arms, or legs. Hyperthyroidism can present with intolerance to heat, hair and skin changes, weight loss, and palpitations. Any of these symptoms should prompt an immediate follow-up visit with the doctor.
Malignancy (Invasive Moles, Choriocarcinoma, Placental Site Trophoblastic Tumor, Ep-ithelioid Trophoblstic Tumor)
The GTNs can be subtle entities in terms of clinical presentation. The physician must keep these on the differential as a cause of common complaints including vaginal bleeding, uterine size discordant to gestation age, pelvic pain, hyperemesis, and miscarriage.
In dramatic clinical presentation of metastatic choriocarcinoma, patients present with symptoms based on the affected organ system. For example, metastasis to the lungs may be associated with hemoptysis, a bloody cough. Metastasis to the brain may present with seizure.
Generally, these entities are identified in the follow-up of molar pregnancies as described later below.
The female ovum and the male sperm are called human gametes. Each gamete carries half of the total genetic information required to form the future fetus. Typically, an ovum will be fertilized by exactly one sperm. Each human gamete carries 23 chromosomes, referred to as a haploid genome. Upon fertilization, the chromosomes from each parent combine and reassemble in complementary pairs of two. The hydatiform moles result from abnormal fertilization of the female ovum by male sperm. There are many aberrant forms of fertilization. Several scenarios are described throughout this report, but the trigger factor for these reactions is unknown. Farther along in this section, we describe the biology of normal pregnancy in more detail to explain where the trophoblastic cell population arises and what its normal role is.
In normal fertilization as described above, the female ovum and the male sperm fuse. They form a zygote. The zygote is a single cell. It is an assembly of the maternal and paternal gametes, each contributing DNA in equal parts. The zygote contains all of the genetic maternal required to form a fetus. This single-cell zygote will divide repeatedly to form clusters of cells with the same genetic make-up. The series of divisions that the zygote undergoes are named depending on their structure and day of development but all of these cells, will differentiate to ultimately form the fetus and its placenta.
The set of cells that form the placenta are called ‘trophoblasts’. Trophoblasts are an invasive species that are responsible for penetrating into the mother’s uterine lining. They are responsible for anchoring the embryo into the uterus. They are also responsible for forming an interface for maternal-fetal oxygen and exchange.
Trophoblasts are generally categorized into two types: cyto-trophoblasts and syncytio-trophoblasts. These two sub-types of cells exist within a developmental stage of the growing embryo called the blastocyst. The blastocyst stage exists at day 5 following fertilization, it is composed of only 16-cells. It can be imagined as a fluid-filled balloon with a small mass of cells contained within. The mass of cells will develop into the fetus and the surface of the balloon represents the placenta. At the blastocyst stage, the forming placenta is composed of an intimate association between the cytotrophoblasts and syncytiotrophoblasts. The cytotrophoblasts form an inner surface layer, around which the syncytiotrophoblasts lay, facing the external environment.
This blastocyst stage of the embryo is an early step in the growth of the embryo, which already demands a highly organized assembly of careful steps. Many pregnancies go unnoticed and a woman may become pregnant but for any of a number of reasons lose the pregnancy before she realizes that her regular cycle has stopped. GTD may be seen after these unrecognized pregnancies that spontaneously miscarry. They may also be seen after a normal, uncomplicated, full-term delivery of a healthy infant.
There is a strikingly, ethnic predisposition to hydatiform moles in groups of women with Asian, Hispanic, and Native American ethnicity. Additionally, women who are adolescents and women over forty years old have a higher risk.
Hydatifirm Mole
The diagnosis of normal versus molar pregnancy might remain unclear until the patient has ultrasound imaging. In the case that a molar pregnancy presents as heavy vaginal bleeding, the diagnosis can mimic miscarriage and only a microscopic analysis of the products of conception may establish the diagnosis.
Hydatidiform moles can be benign with a malignancy risk (ie: partial or complete moles) or frankly malignant (ie: invasive moles). The malignant character is established on follow-up, based on whether the mole persists or not after uterine evacuation, whether distant metastases are present. Generally, no biopsy will be obtained to differentiate between these molar entities.
Because trophoblast cells produce the hormone beta-human choriogonadotropin ( -hCG), commonly referred to as ‘the pregnancy hormone’, the easiest manner in which to track resolution of hydatiform moles is by measuring -hCG over time. If -hCG levels do not normalize rapidly after treatment, malignancy is suspected and a search to localize or rule out the persistent entity begins. Of complete hydatidiform mole, 20% are malignant and persistent, about 5% metastasize. Regarding partial moles, only about 2-3% are malignant.
Choriocarcinoma
In women of reproductive age with abnormal bleeding, -hCG is checked to rule out pregnancy and the GTD. For women who have recently delivered, bleeding in the postpartum period is normal. However, bleeding persistent over six weeks after delivery less usual and evaluated for GTD. Levels of -hCG may be quantified and tracked over time as previously mentioned. A down-trending of values indicates no persistent trophoblastic tissue. Should the values of -hCG plateau or even rise after a recognized conception, the diagnosis of GTN is assigned. The diagnosis of choriocarcinoma is based on persistent -hCG with a suspicious lesion on imaging. These tumors tend to bleed heavily when disrupted. They are therefore not often biopsied like other tumors.
Rare Variants
The PSTT and ETT are generally diagnosed at the time of pathologic examination after biopsy or surgical excision. These entities may be associated with low-normal elevations in -hCG but never elevations as large as are seen in choriocarcinomas. They are often identified when the placenta is sent for microscopic analysis by a pathologist after an abnormal architecture is noticed in the delivery room. PSTT may secrete the hormone, human chorionic lactogen (hPL). This hormone may be identified in blood sampled and used to inform a diagnosis but rarely used in clinical practice. ETT carry no such marker.
Clinical Testing and Work-Up
The physician is likely to order routine blood tests, serum -hCG levels, renal and liver function tests and a CT or chest x-ray. It is important to note that choriocarcinoma develops a particularly rich blood supply that carries a dangerous propensity to spread to the lungs, brain, liver, pelvis, vagina, spleen, intestines, kidneys.
When a lesion is excised surgically, it is sent to the pathology laboratory for careful examination. The sample can be fixed and stained to identify general changes in cell architecture. An examination into the way that the tumor cells are arranged and behave can indicate which variant of GTD, if any, the patient has. The specimen can also be stained by immunohistochemistry. Immunohistochemistry is a method of staining a sample for different cellular markers using a targeted antibody connected, conjugated to a color tag. The markers that are useful in identifying a case of trophoblastic disease include cytokeratin18, HLA-G, -hCG, hPL, Mel-CAM, p63, and Ki-67. The expected staining outcomes for the GTD are described below but the cellular functions of the given markers are far beyond the scope of this report and omitted.
Benign Hydatiform Mole
The follow-up of uncomplicated (non-malignant) hydatidiform mole is weekly serum -hCG levels until three consecutive normal values are obtained. This is followed by monthly measurement of serum hCG levels for six months.
Invasive Mole
The invasive mole begins to take on an amorphous mass, which loses some of the villi characteristic of normal placenta and hydatiform moles. The entity is rich in tropho-blastic cells and expands through the uterus into the myometrium. Invasive moles mimic points of placenta accreta. Placenta accreta is the abnormal implantation of otherwise normal placenta to the muscular layer of the uterus. It is often also associated with sites of uterine scarring, as associated with previous Cesarean section or myomectomy for leiomyomata. The diagnosis of invasive mole is actually seldom made since it re-quires a hysterectomy to be able to show that the molar tissue (villi and trophoblasts) invaded and destroyed the myometrium.
Choriocarcinoma
Choriocarcinoma is an entity with high replicative turnover. There is an intimate association of syncitotrophoblasts and cytotrophoblasts that outgrow their blood supply and start to become necrotic. Choriocarcinoma tumors often have internal hemorrhage. The syncytiorophoblast component is often described as having a lace-like appearance along the maternal blood-filled lacunae, which bring oxygenated blood from the mother to the fetus. Patients with GTN (i.e., malignancy) are followed with weekly serum hCG levels until three to four consecutive normal values are obtained. This is followed by measurement of serum -hCG levels monthly for one year. Pregnancy is avoided dur-ing the period of follow-up. A subsequent pregnancy is confirmed by an early ultra-sound.
Rare Variants
PSTT is composed of bland, polygonal trophoblastic cells that arrange in sheets or cords. These cells replicate relatively slowly and do not necrose or hemorrhage the way that choriocarcinoma does.
ETT can be a solid or cystic mass. The trophoblasts arrange in nests, cords and surround blood vessels. They have a pink, eosinophilic extracellular matrix. These cells replicate moderately fast and demonstrate necrosis in a unique pattern termed ‘geo-graphic necrosis’.
Laboratory Examination Details
In terms of the work-up conducted by the pathology laboratory, there are a number of cellular markers that can be investigated to definitively differentiate one trophoblastic disease entity from another. Trophoblastic disease can be verified when samples stain positive for cytokeratin-18 and HLA-G. Choriocarcinoma can be definitively diagnosed with a strong -hCG stain. PSTT and EPS stain positively for hPL and Mel-CAM, nega-tively for p63. PSTT will stain positive for Ki-67 in over 1% of cells while EPS will stain positive for Ki-67 in <1% of cells. ETT and PSN stain negative for hPL and Mel-CAM, positively for p63 and are differentiated Ki-67. Ki-67 will be positive in over 10% of cells in a ETT while positive in less than 10% of cells in PSN.
First Line Treatment
In patients with molar pregnancy (partial or complete), reliable methods of treatment primarily include suction dilation and curettage or evacuation (D&C or D&E). The procedure may be done with ultrasound image-guidance, and with or without IV oxytocin. Oxytocin is an optional medication that helps the uterus to contract and expels molar tissue. D&C has an associated with a risk of uterine scarring, which can complicate later pregnancies.
Medical treatment is often the first line for malignant entities. This consists of a short course of a single medication that aims to stop the replication of rapidly dividing cells. The medication most often used is methotrexate. Methotrexate is also used as an anti-cancer drug against solid malignancy (eg: breast, lung) and liquid tumors (leukemia, lymphoma). Methotrexate is also known as a disease-modifying treatment for some au-toimmune disorders (lupus, psoriasis, rheumatoid arthritis ext).
Actinomycin D is another available agent. It is often reserved for the patients whose disease does not resolve with methotrexate treatment. Actinomycin D has been suggested to carry a slightly higher cure rate than methotrexate but has also been associated with increased incidence of severe side effects. Both agents affect the blood and immune system, as well as the kidneys. Methotrexate however also affects the liver. If a patient has liver disease, this may be one reason that the treating physician may choose actinomycin D as first line treatment. Finally, two more drugs are used, generally across Asia, in the single-agent treatment of GTD. Etopside is avoided in the United States because it carries the risk of causing secondary malignancies including. leukemia, breast cancer, colon cancer, and melanoma. Finally, fluorouracil can also be used alone in the treatment of GTD. Should single-agent treatment prove ineffective, multi-agent chemotherapy may also be used, should the patient not want, or be able to have, surgery. The treatment of persistent GTD is discussed below alongside the treatment of malignant GTD.
Prognosis
The prognosis and treatment of malignant GTD is determined according to a standardized tumor staging. The staging system used for GTD was developed by the International Federation or Obstetrics and Gynecology, better known also as the Federation Internationale de Gynecologie et d’Obstetrique (FIGO). The FIGO staging system includes a risk score developed by the World Health Organization (WHO). This staging system takes different factors into account such as patient age, source of GTD (molar pregnancy, abortion, term delivery), months since product of conception was identified and tumor anatomy (size, metastases). Of note, the FIGO staging system is applied to the treatment of choriocarcinoma but notably not applied to patients with placental site or epithelial trophoblastic tumors.
The FIGO-WHO stratification system designates patients as having either low- or high-risk in regards to the probability to have a poor response to treatment. Patients with low- and high-risk GTD can both have metastatic disease.
Low-risk GTD is highly responsive to single-agent chemotherapy. Even if a patient develops resistance to the first single-agent chemotherapy they are started on, there is a strong likelihood that they will respond well to a second agent. Patients with low-risk GTD that have metastases are at greater risk for initial non-response to treatment. Physicians may choose to turn to the -hCG levels in a patient’s blood and decided to jump directly to a multi-agent treatment for patients with low-risk GTD. Generally, the cut-off of -hCG >300IU/L at time of treatment initiation will encourage physicians to start the EMA-CO regimen. EMA-CO consists of combination etopside, methotrexate, actinomycin D, cyclophosphamide, and vincristine. Below the given cut-off, the single-agent treatment is successful and multiple-agent exposure does not merit the associated toxicity.
Patients with high-risk GTD are started in EMA-CO for first line treatment. There is a significant percent however, that will require alternative treatments after non-response. No single second-line agents have proven superior to others in this clinical scenario and many of the choices are therapies re-adapted from other cancer treatments. The success seen in this series of second-line regimens used in refractory, high-risk GTD are discussed under investigational therapies.
Long-Term Health
Regardless of the initial diagnosis, it is important that patients with previous GTD care-fully follow up with their health care providers after treatment to track the levels of -hCG in the blood. These levels should drop with a successful curettage. If the levels of -hCG plateau or begin to rise again, persistent disease is suspected. -hCG values within normal ranges for three consecutive weeks indicate remission, expected to be maintained monthly for six months then yearly for up to 3 years. Disease recurrence is most common in the first year after treatment. This timeline can be reduced from one year to six months if the woman is over 35 years old and desires to conceive. If it otherwise very important that patients abstain from pregnancy while in one-year follow-up for GTD as -hCG is also made by the growing embryo and thus can mistakenly suggest recurrence.
Regarding PSTTs and ETTs, surgery is the primary approach to a cure. Chemotherapy is importantly ineffective in these malignancies. The primary lesion may be extensive and require a hysterectomy. Any metastases must be identified and likewise removed surgically before their size increases to cause destructive pressures on the surrounding tissue.
In the treatment of these lesions, it is also important to think also of the well-being of any fetus to be conceived in the future. It is important to review some basic immunology. Cells are covered in different proteins that serve to mark the cells as belonging to one’s own body and as non-foreign. The proteins covering the cells protect ‘self’ cells from being attacked and destroyed by the immune system. These proteins are described according to different type-systems such as the ABO and Rhesus (Rh)-factor systems. When a woman conceives a fetus or develops a molar pregnancy, she runs the risk of exposure to non-self-blood cells. Specifically, women with Rh-negative blood types may be exposed to blood cells that are Rh-positive. Because the woman’s cells do not recognize Rh-proteins as belonging to their own body, they form antibodies to destroy any cells with Rh-positive markers. This exposure to non-self-blood is not immediately dangerous for the mother. If the mother with Rh-negative blood is exposed to Rh-positive blood and forms antibodies against Rh-positive blood, subsequent pregnancies she carries are at risk. The antibodies formed in the first pregnancy re-main in her blood and may attack that fetus’ forming blood supply if it is Rh-positive. This can result in fetal anemia, heart-failure, and even death. Patients with Rh-negative blood type, at risk for exposure to Rh-positive blood products, should receive anti-Rh immune globulin. This medication can potentially protect the woman from forming her antibodies against Rh-factor. This medication is known to work best when ad-ministered within 72 hours of a person’s exposure to non-Rh-compatible blood.
As with many rare diseases, it is difficult to organize large, prospective, randomized clinical trials. The majority of what is known is often based on single or several patient case reports published out of different institutions. Nevertheless, important information can be gleaned from these smaller studies.
Some data, albeit limited, suggests that there are a few single-agent therapies for pa-tients with refractory, high-risk GTD. These agents include paclitaxel, capecitabine, and pegylated liposomal doxorubicin.
Multi-agent therapy includes TE-TP (paclitaxel with alternating weeks of topside and cisplatin), PC (paclitaxel and carboplatin), BEP (bleomycin, etopside, and cisplatin), ICE (ifosfamide, etopside, cisplatin), PVB (cisplatin, vinblastin, and bleomycin), FUDR (floxuridine, actinomycin D, etopside, and vindesine), and fluorouracil with actinomy-cin D. One major concern, is that any regimen containing etopside is associated with secondary malignancy risk, especially breast and colon cancer, leukemia, lymphoma, and melanoma. FUDR is a particularly promising regimen, reported to induce remission in all patients with GTD taking it and even some patients with PSTT.
Two additional agents under newly under investigation, and include poemsrolizumab and aveluab. These are synthetic antibodies against PDL-1 receptors that exist over the surface of malignant GTD cells. PDL-1 serves as an inhibitor to programmed cell death. Cytotoxic T cells are a type of immune cell responsible for the elimination of unwanted cells from within the body, including ones which maybe pathogen-infected or cancerous. Cells can interact by the direct binding of proteins on their cell mem-branes. T-cells interact in this was with target cells. They bind the cells they are inter-ested to investigate. The aim is for the T-cell, cell surface protein, PD-1 with the target cell, cell surface protein, PDL-1 receptor. If PD-1 binds PDL-1, the T-cell interprets the target cell to be a normal, ‘self’ cell. In the event that PD-1 does not bind PDL-1, the T-cell considered the target as being unwarned and will induced cell death in the sup-posedly infected, invading, or cancerous cell. Like other cancerous cells, GTD cells carry many PDL-1 receptors that protect it from immune cell targeting. Synthetic anti-bodies against the PDL-1 on these cells can mask the protective function of PDL-1 and allow the immune system to target these cells for destruction.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. This site provides summaries and investigator contact information on both actively enrolling and completed clinical trials, with results where available.
New open trials and trial results are constantly being updated. Patients are encouraged to check postings regularly.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD web-site:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Placental Pathology: Atlas of Nontumor Pathology. 3rd ed. Arlington, Virginia: American Registry of Pathology; 2005.
Heerema-McKenny, Popek, De Paepe. Diagnostic Pathology: Placenta. 1st ed. Else-vier; 2014.
JOURNAL ARTICLES
Lurain JR. Gestational trophoblastic disease II: classification and management of ges-tational trophoblastic neoplasia. A J Obstet Gynecol. 2011 Jan; 204(1):11-8.
Lurain JR. Gestational trophoblastic disease I: Epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. A J Obstet Gynecol. 2010 Dec; 203(6):531-9.
INTERNET
Berkowitz, RS, Golstein DP, Horowitz, NS. Hydatiform mole: Epidemiology, clinical fea-tures, and diagnosis. Last updated: April 14, 2017. UpToDate. https://www.uptodate.com/contents/hydatidiform-mole-epidemiology-clinical-features-and-diagnosis Accessed April 29, 2019.
Berkowitz, RS, Golstein DP, Horowitz, NS. Hydatiform mole: Management. UpToDate. Last updated: April 14, 2017. https://www.uptodate.com/contents/hydatidiform-mole-management Accessed April 29, 2019.
Berkowitz, RS, Golstein DP, Horowitz, NS. Gestational trophoblastic neoplasia: epide-miology, clinical features, diagnosis, staging and risk stratification. UpToDate. Last up-dated: September 17, 2017. https://www.uptodate.com/contents/gestational-trophoblastic-neoplasia-epidemiology-clinical-features-diagnosis-staging-and-risk-stratification Accessed April 29, 2019.
Baergen, RN. Gestational trophoblastic disease: pathology. UpToDate. Last updated: March 19, 2017. https://www.uptodate.com/contents/gestational-trophoblastic-disease-pathology Accessed April 29, 2019.
Berkowitz, RS, Golstein DP, Horowitz, NS. Initial management of low-risk gestational trophoblastic neoplasia. UpToDate. Last updated: July 11, 2017. https://www.uptodate.com/contents/initial-management-of-low-risk-gestational-trophoblastic-neoplasia Accessed April 29, 2019.
Berkowitz, RS, Golstein DP, Horowitz, NS. Initial management of high-risk gestational trophoblastic disease. UpToDate. Last updated April 6, 2017. https://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia Accessed April 29, 2019.
Berkowitz, RS, Golstein DP, Horowitz, NS. Management of resistant or recurrent gesta-tional trophoblastic neoplasia. UpToDate. Last updated December 19, 2017. https://www.uptodate.com/contents/management-of-resistant-or-recurrent-gestational-trophoblastic-neoplasia Accessed April 29, 2019.
Goff, B. Human chorionic gonadotropin: Testing in pregnancy and gestational tropho-blastic disease and causes of low persistent levels. Last update: April 27, 2016. Up-ToDate. https://www.uptodate.com/contents/human-chorionic-gonadotropin-testing-in-pregnancy-and-gestational-trophoblastic-disease-and-causes-of-low-persistent-levels Accessed April 29, 2019.
Moise, KJ. Prevention of Rhesus (D) alloimmunization in pregnancy. UpToDate. Last updated: January 5, 2018. https://www.uptodate.com/contents/prevention-of-rhesus-d-alloimmunization-in-pregnancy Accessed April 29, 2019.
Gestational Trophoblastic Disease—Patient Version. National Cancer Institute. https://www.cancer.gov/types/gestational-trophoblastic Accessed April 29, 2019.
NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.
Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/