Gestational Trophoblastic Disease







  • Chapter Outline



  • Introduction 784



  • Overview of Early Placental Development 784




    • Villous Trophoblast 784



    • Extravillous (Intermediate) Trophoblast 785



    • Trophoblast Immunohistochemical Markers 787




  • Molar Gestational Trophoblastic Disease 788




    • Complete Hydatidiform Mole 788



    • Early (First Trimester) Complete Hydatidiform Moles 791



    • Advanced (Second Trimester) Complete Hydatidiform Moles 791



    • Partial Hydatidiform Mole 795



    • Adverse Clinical Outcomes in Molar Disease 798




  • Trophoblastic Neoplasia 800




    • Choriocarcinoma 800



    • Choriocarcinoma Associated with Full-term Pregnancy and Intraplacental Choriocarcinoma 802



    • Placental Site Trophoblastic Tumor 803



    • Epithelioid Trophoblastic Tumor 805




  • Non-Neoplastic Trophoblastic Lesions 807




    • Placental Site Nodule or Plaque 807



    • Exaggerated Placental Site (Reaction) 809





Introduction


Gestational trophoblastic disease is a spectrum of disorders ranging from unusual presentations of normal implantation, through premalignant hydatidiform moles (complete, partial, and invasive mole) to malignant disorders including choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor ( Table 34.1 ). Often, trophoblast remnants of normal gestations, including placental site nodules, and exaggerated placental site reaction may cause clinical symptoms, which can be clinically and histologically confused with trophoblastic tumors. Although each of these entities has its own clinical and pathologic characteristics, they may be grouped under the single umbrella of gestational trophoblastic disease because they are all related to pregnancy, and may progress from one to another.



Table 34.1

World Health Organization Classification of Gestational Trophoblastic Disease















Non-Neoplastic, Non-Molar Trophoblastic Lesions



  • Placental site nodule



  • Exaggerated placental site

Hydatidiform Moles (Abnormally Formed Placentas)



  • Complete mole



  • Partial mole



  • Invasive mole

Trophoblastic Tumors (Neoplastic Diseases)



  • Choriocarcinoma



  • Placental site trophoblastic tumor



  • Epithelioid trophoblastic tumor





Overview of Early Placental Development


Histologic findings in trophoblastic disease often recapitulate those of the early placenta, causing difficulty in distinction between a disease state and normal gestational or postgestational trophoblast remnants. For this reason, it will be helpful to review early phases of normal placental development to understand the cells of origin, and those cytomorphologic features that are useful to distinguish normal from abnormal trophoblast.


Villous Trophoblast


At the end of the first week following conception, trophectoderm of the blastocyst implants in the endometrial surface and invades the endometrial stroma. The mononuclear trophoblastic shell, composed of previllous trophoblast, has not yet formed villous structures. This is responsible for erosion of maternal tissue by production of various hormones, cytokines, a number of extracellular matrix receptors, and matrix-degrading proteases and their inhibitors. The previllous trophoblast of the implanting embryonic pole differentiates into two components, the outer syncytiotrophoblast located at the maternal–fetal interface and the inner cytotrophoblast ( Figure 34.1 ). The cytotrophoblast is an inner layer of ovoid, mononuclear cells with high proliferative activity that functions as the trophoblastic stem cell. Syncytiotrophoblast, the first differentiated trophoblast lineage, produces human chorionic gonadotropin (hCG) and proteolytic enzymes, and secretes factors that cause apoptosis of the endometrial epithelial cells and decidua. Penetration and erosion of the adjacent maternal capillaries results in the formation of lacunae within the syncytiotrophoblast, and these structures enlarge to form the intervillous space.




Figure 34.1


Lacunar stage in early placental development. As the trophoblastic cells invade the endometrium, they differentiate to form a double layer of cytotrophoblast (C) and syncytiotrophoblast (S) and intervening lacunar space (L).


Early in the third week, extraembryonic mesoderm grows into the solid primary villous trabeculae of cytotrophoblast and syncytiotrophoblast ( Figure 34.2 ), forming secondary villi. These consist of an outer layer of syncytiotrophoblast, a middle layer of cytotrophoblast, and an inner connective tissue core. At this stage secondary chorionic villi cover the entire surface of the chorionic sac.




Figure 34.2


Villous stage in placental development. Mesenchymal cells derived from extraembryonic mesoderm (M) invade the villi, transforming the primary villi (P) into secondary villi (S).


Active vasculogenesis begins within the secondary villous stroma, transforming them into tertiary villi ( Figure 34.3A–D ). Early primitive capillaries in the villous core are formed by in situ differentiation of pluripotent mesodermal tissue into hemangioblastic stem cells that give rise to committed endothelial progenitors (angioblast) and hematopoietic stem cells. Angioblasts form angiogenic cell cords ( Figure 34.3A ), which develop slit-like vascular lumens during the third to fourth week ( Figure 34.3B ). Subsequently, distinct vascular lumens with variable numbers of immature hemato­poietic cells begin to appear ( Figure 34.3C ). Frequent mitotic figures and occasional karyorrhexis are identified among the angiogenic cell cords and the stromal cells at this stage. After that, new blood vessels in the villous stroma are derived by sprouting, elongation, and remodeling of already existing blood vessels. Villous stroma is basophilic and myxomatous until the end of the fourth week when the ground substance gradually assumes an edematous and reticular appearance ( Figure 34.3D ).




Figure 34.3


Vasculogenetic steps in chorionic villi during early pregnancy (A–D) . Stromal vessels are differentiated from ( A ) immature angiogenic cell cords (arrow) within basophilic stroma to ( B ) immature blood vessels containing primitive slit-like vascular lumens and immature hematopoietic components to ( C, D ) mature blood vessels containing distinct vascular lumens and hematopoietic components. Note stromal changes from basophilic to edematous stroma.








As active vasculogenesis is occurring, the villi branch, trophoblast proliferates at the implanting embryonic pole, and forms a confluent shell along the external circumference of the chorionic villi ( Figure 34.4 ). This cytotropho­blastic shell of early pregnancy mimics the trophoblastic hyperplasia of hydatidiform moles, with which it should not be confused.




Figure 34.4


Normal placenta during the early gestation showing exuberant polarized and circumferential trophoblastic proliferation merging into a peripheral cytotrophoblastic shell (left).


Extravillous (Intermediate) Trophoblast


Extravillous trophoblast is a general term for the entire population of trophoblast residing outside the villi, including implantation site (basal plate), chorion laeve, chorionic plate (subchorionic area), and placental septum. It is commonly designated as ‘intermediate trophoblast’ by pathologists. The terms extravillous and intermediate trophoblast will be used interchangeably in this chapter.


While one group of cytotrophoblast fuses to form multinucleated syncytiotrophoblast, which encases the free villi of the placenta, another differentiates into extravillous trophoblast and develops invasive properties. At the basal end of anchoring villi, cytotrophoblast proliferates to form columns of ‘villous intermediate trophoblast,’ a cohesive mass of cells with high proliferative activity ( Figure 34.5A ). As the cells in the trophoblastic column come into contact with decidua, these cells exit the cell cycle, thereby losing their proliferative activity, detach from the cell column, and acquire migratory and invasive properties. Subsequently, the cells move into the decidua and superficial myometrium (interstitial trophoblast) ( Figure 34.5B ) and penetrate the decidual spiral arteries (endovascular trophoblast) ( Figure 34.5C ). These are collectively referred to as ‘implantation site intermediate trophoblast.’




Figure 34.5


Villous and extravillous trophoblast at the implantation site. (A) Anchoring villi (AV) are attached to the decidua of the implantation site. (B) Extravillous (interstitial) trophoblast (closed arrows) infiltrating into the decidua have densely eosinophilic or amphophilic cytoplasm. (C) Extravillous (endovascular) trophoblast (EVT) infiltrating into the blood vessels. (D) Close-up view of extravillous trophoblast (closed arrows) shows slightly larger, irregular, and hyperchromatic nuclei with more eosinophilic or amphophilic cytoplasm than the admixed decidual cells with paler cytoplasm (open arrows).








In a normal implantation site, endovascular trophoblast displaces the endothelial lining and musculoelastic tissue of spiral arteries, increasing the luminal diameter and allowing greater transport of maternal blood to the intervillous space. Proliferative and invasive ability do not coexist in one and the same cell of normal trophoblast, but rather are seen in mutually exclusive populations. This contrasts with ‘malignant’ trophoblast, where the invasive cells also proliferate.


Interstitial (intermediate) trophoblast cytology is similar to that of surrounding decidualized stromal cells ( Figure 34.5A–D ), but the trophoblast nuclei are slightly larger, irregular, and hyperchromatic. Trophoblastic spindle cells often have angular dark nuclei as they dissect individually or in small clusters between decidual cells ( Figure 34.5D ).


Chorionic villi cover the entire chorionic sac until the beginning of the eighth week but become asymmetrical as those associated with the decidua capsularis begin to degenerate. A variable thickness of trophoblastic cells persists in the chorion laeve until term, but this extravillous tropho­blast is not invasive. Therefore, the fetal membrane is composed of amniotic epithelium sitting on thin connective tissue layers of amnion and chorion, maternal decidua parietalis with interposed extravillous trophoblast, and occasional ghost villi ( Figure 34.6A ). Microscopically, intermediate trophoblast in the chorion laeve of term placentas are composed of two populations with differing cytology and immunophenotypes ( Figure 34.6A–F ). These two types of intermediate trophoblast are not strictly separated into different compartments, but rather are admixed to some extent.




Figure 34.6


Cytomorphologic features and immunophenotypes of extravillous trophoblast. Trophoblast contacting chorionic stroma are relatively smaller and uniform with clear cytoplasm ( A , closed arrow), while those directly contacting decidua have slightly larger nuclei and amphophilic cytoplasm ( A , open arrow). P63 is only expressed in the former ( B , open arrow), whereas CD146 (Mel-CAM) is mostly expressed in the latter ( C , open arrow). Extravillous trophoblast in the implantation site (basal plate) is also composed of two populations (D) . P63 is expressed in the smaller trophoblasts with clear cytoplasm ( E , open arrow) and CD146 (Mel-CAM) is expressed in the larger trophoblasts with amphophilic cytoplasm ( F , closed arrow).












Trophoblast Immunohistochemical Markers


Non-neoplastic trophoblastic lesions can be confused with a variety of trophoblastic and nontrophoblastic tumors because of their inherent cytologic atypia and pleomorphism. Immunohistochemical markers can be helpful in resolving the differential diagnosis.


All trophoblastic cells, including cytotrophoblast, syncytiotrophoblast, and intermediate trophoblast, possess epithelial antigens detected by antibodies for cytokeratin (AE1 and AE3), epithelial membrane antigen, and low molecular weight cytokeratins (CAM 5.2 and Ber-P4). Although not specific to the trophoblast, these common antibodies are useful to distinguish trophoblastic from nonepithelial tumors, such as epithelioid smooth muscle neoplasia. Some antibodies, including HSD3β1, HLA-G, and β-hCG, are used in the differential diagnosis between trophoblastic and nontrophoblastic lesions. Others, including P63, placental alkaline phosphatase, human placental lactogen, and CD146 (Mel-CAM), are useful to infer ‘chorionic-type’ or ‘implantation site’ differentiation among intermediate trophoblast. Expressions of various trophoblastic markers in subpopulations of trophoblast are summarized in Panel A of Table 34.2 , and their use in resolving various differential diagnoses is shown in Panel B.



Table 34.2

Trophoblast Immunomarkers (Panel A) and a Diagnostic Algorithm for Their Use in Differential Diagnosis (Panel B)






































































Panel A
Differential Diagnosis Trophoblastic Versus Nontrophoblastic Chorionic-Type Versus Implantation Site IT
Marker HSD3β1 HLA-G β-hCG P63 PLAP hPL CD146
Cytotrophoblast + +
Syncytiotrophoblast + + + +
Implantation site IT + + ± + +
Chorionic-type IT + + + +
Nontrophoblastic epithelial cells ± Variable Variable
IT, intermediate trophoblast; PLAP, placental alkaline phosphatase; hPL, human placental lactogen.
Panel B







Villous Trophoblast


At the end of the first week following conception, trophectoderm of the blastocyst implants in the endometrial surface and invades the endometrial stroma. The mononuclear trophoblastic shell, composed of previllous trophoblast, has not yet formed villous structures. This is responsible for erosion of maternal tissue by production of various hormones, cytokines, a number of extracellular matrix receptors, and matrix-degrading proteases and their inhibitors. The previllous trophoblast of the implanting embryonic pole differentiates into two components, the outer syncytiotrophoblast located at the maternal–fetal interface and the inner cytotrophoblast ( Figure 34.1 ). The cytotrophoblast is an inner layer of ovoid, mononuclear cells with high proliferative activity that functions as the trophoblastic stem cell. Syncytiotrophoblast, the first differentiated trophoblast lineage, produces human chorionic gonadotropin (hCG) and proteolytic enzymes, and secretes factors that cause apoptosis of the endometrial epithelial cells and decidua. Penetration and erosion of the adjacent maternal capillaries results in the formation of lacunae within the syncytiotrophoblast, and these structures enlarge to form the intervillous space.




Figure 34.1


Lacunar stage in early placental development. As the trophoblastic cells invade the endometrium, they differentiate to form a double layer of cytotrophoblast (C) and syncytiotrophoblast (S) and intervening lacunar space (L).


Early in the third week, extraembryonic mesoderm grows into the solid primary villous trabeculae of cytotrophoblast and syncytiotrophoblast ( Figure 34.2 ), forming secondary villi. These consist of an outer layer of syncytiotrophoblast, a middle layer of cytotrophoblast, and an inner connective tissue core. At this stage secondary chorionic villi cover the entire surface of the chorionic sac.




Figure 34.2


Villous stage in placental development. Mesenchymal cells derived from extraembryonic mesoderm (M) invade the villi, transforming the primary villi (P) into secondary villi (S).


Active vasculogenesis begins within the secondary villous stroma, transforming them into tertiary villi ( Figure 34.3A–D ). Early primitive capillaries in the villous core are formed by in situ differentiation of pluripotent mesodermal tissue into hemangioblastic stem cells that give rise to committed endothelial progenitors (angioblast) and hematopoietic stem cells. Angioblasts form angiogenic cell cords ( Figure 34.3A ), which develop slit-like vascular lumens during the third to fourth week ( Figure 34.3B ). Subsequently, distinct vascular lumens with variable numbers of immature hemato­poietic cells begin to appear ( Figure 34.3C ). Frequent mitotic figures and occasional karyorrhexis are identified among the angiogenic cell cords and the stromal cells at this stage. After that, new blood vessels in the villous stroma are derived by sprouting, elongation, and remodeling of already existing blood vessels. Villous stroma is basophilic and myxomatous until the end of the fourth week when the ground substance gradually assumes an edematous and reticular appearance ( Figure 34.3D ).




Figure 34.3


Vasculogenetic steps in chorionic villi during early pregnancy (A–D) . Stromal vessels are differentiated from ( A ) immature angiogenic cell cords (arrow) within basophilic stroma to ( B ) immature blood vessels containing primitive slit-like vascular lumens and immature hematopoietic components to ( C, D ) mature blood vessels containing distinct vascular lumens and hematopoietic components. Note stromal changes from basophilic to edematous stroma.








As active vasculogenesis is occurring, the villi branch, trophoblast proliferates at the implanting embryonic pole, and forms a confluent shell along the external circumference of the chorionic villi ( Figure 34.4 ). This cytotropho­blastic shell of early pregnancy mimics the trophoblastic hyperplasia of hydatidiform moles, with which it should not be confused.




Figure 34.4


Normal placenta during the early gestation showing exuberant polarized and circumferential trophoblastic proliferation merging into a peripheral cytotrophoblastic shell (left).




Extravillous (Intermediate) Trophoblast


Extravillous trophoblast is a general term for the entire population of trophoblast residing outside the villi, including implantation site (basal plate), chorion laeve, chorionic plate (subchorionic area), and placental septum. It is commonly designated as ‘intermediate trophoblast’ by pathologists. The terms extravillous and intermediate trophoblast will be used interchangeably in this chapter.


While one group of cytotrophoblast fuses to form multinucleated syncytiotrophoblast, which encases the free villi of the placenta, another differentiates into extravillous trophoblast and develops invasive properties. At the basal end of anchoring villi, cytotrophoblast proliferates to form columns of ‘villous intermediate trophoblast,’ a cohesive mass of cells with high proliferative activity ( Figure 34.5A ). As the cells in the trophoblastic column come into contact with decidua, these cells exit the cell cycle, thereby losing their proliferative activity, detach from the cell column, and acquire migratory and invasive properties. Subsequently, the cells move into the decidua and superficial myometrium (interstitial trophoblast) ( Figure 34.5B ) and penetrate the decidual spiral arteries (endovascular trophoblast) ( Figure 34.5C ). These are collectively referred to as ‘implantation site intermediate trophoblast.’




Figure 34.5


Villous and extravillous trophoblast at the implantation site. (A) Anchoring villi (AV) are attached to the decidua of the implantation site. (B) Extravillous (interstitial) trophoblast (closed arrows) infiltrating into the decidua have densely eosinophilic or amphophilic cytoplasm. (C) Extravillous (endovascular) trophoblast (EVT) infiltrating into the blood vessels. (D) Close-up view of extravillous trophoblast (closed arrows) shows slightly larger, irregular, and hyperchromatic nuclei with more eosinophilic or amphophilic cytoplasm than the admixed decidual cells with paler cytoplasm (open arrows).








In a normal implantation site, endovascular trophoblast displaces the endothelial lining and musculoelastic tissue of spiral arteries, increasing the luminal diameter and allowing greater transport of maternal blood to the intervillous space. Proliferative and invasive ability do not coexist in one and the same cell of normal trophoblast, but rather are seen in mutually exclusive populations. This contrasts with ‘malignant’ trophoblast, where the invasive cells also proliferate.


Interstitial (intermediate) trophoblast cytology is similar to that of surrounding decidualized stromal cells ( Figure 34.5A–D ), but the trophoblast nuclei are slightly larger, irregular, and hyperchromatic. Trophoblastic spindle cells often have angular dark nuclei as they dissect individually or in small clusters between decidual cells ( Figure 34.5D ).


Chorionic villi cover the entire chorionic sac until the beginning of the eighth week but become asymmetrical as those associated with the decidua capsularis begin to degenerate. A variable thickness of trophoblastic cells persists in the chorion laeve until term, but this extravillous tropho­blast is not invasive. Therefore, the fetal membrane is composed of amniotic epithelium sitting on thin connective tissue layers of amnion and chorion, maternal decidua parietalis with interposed extravillous trophoblast, and occasional ghost villi ( Figure 34.6A ). Microscopically, intermediate trophoblast in the chorion laeve of term placentas are composed of two populations with differing cytology and immunophenotypes ( Figure 34.6A–F ). These two types of intermediate trophoblast are not strictly separated into different compartments, but rather are admixed to some extent.




Figure 34.6


Cytomorphologic features and immunophenotypes of extravillous trophoblast. Trophoblast contacting chorionic stroma are relatively smaller and uniform with clear cytoplasm ( A , closed arrow), while those directly contacting decidua have slightly larger nuclei and amphophilic cytoplasm ( A , open arrow). P63 is only expressed in the former ( B , open arrow), whereas CD146 (Mel-CAM) is mostly expressed in the latter ( C , open arrow). Extravillous trophoblast in the implantation site (basal plate) is also composed of two populations (D) . P63 is expressed in the smaller trophoblasts with clear cytoplasm ( E , open arrow) and CD146 (Mel-CAM) is expressed in the larger trophoblasts with amphophilic cytoplasm ( F , closed arrow).














Trophoblast Immunohistochemical Markers


Non-neoplastic trophoblastic lesions can be confused with a variety of trophoblastic and nontrophoblastic tumors because of their inherent cytologic atypia and pleomorphism. Immunohistochemical markers can be helpful in resolving the differential diagnosis.


All trophoblastic cells, including cytotrophoblast, syncytiotrophoblast, and intermediate trophoblast, possess epithelial antigens detected by antibodies for cytokeratin (AE1 and AE3), epithelial membrane antigen, and low molecular weight cytokeratins (CAM 5.2 and Ber-P4). Although not specific to the trophoblast, these common antibodies are useful to distinguish trophoblastic from nonepithelial tumors, such as epithelioid smooth muscle neoplasia. Some antibodies, including HSD3β1, HLA-G, and β-hCG, are used in the differential diagnosis between trophoblastic and nontrophoblastic lesions. Others, including P63, placental alkaline phosphatase, human placental lactogen, and CD146 (Mel-CAM), are useful to infer ‘chorionic-type’ or ‘implantation site’ differentiation among intermediate trophoblast. Expressions of various trophoblastic markers in subpopulations of trophoblast are summarized in Panel A of Table 34.2 , and their use in resolving various differential diagnoses is shown in Panel B.



Table 34.2

Trophoblast Immunomarkers (Panel A) and a Diagnostic Algorithm for Their Use in Differential Diagnosis (Panel B)






































































Panel A
Differential Diagnosis Trophoblastic Versus Nontrophoblastic Chorionic-Type Versus Implantation Site IT
Marker HSD3β1 HLA-G β-hCG P63 PLAP hPL CD146
Cytotrophoblast + +
Syncytiotrophoblast + + + +
Implantation site IT + + ± + +
Chorionic-type IT + + + +
Nontrophoblastic epithelial cells ± Variable Variable
IT, intermediate trophoblast; PLAP, placental alkaline phosphatase; hPL, human placental lactogen.
Panel B







Molar Gestational Trophoblastic Disease


Hydatidiform moles are abnormal gestations created by an imbalance of parental genomes secondary to abnormal fertilization events, most commonly androgenetic diploid (complete moles) or biparental triploid (partial moles). They are significant as examples of failed pregnancy that may recur at heightened risk, and as premalignant lesions that justify observational or therapeutic intervention. Depending on the nature of the genomic imbalance, which is reflected in the histologic appearance, some may display invasive or metastatic behavior, or progress to overtly malignant choriocarcinoma. All hydatidiform moles have an edematous villous stroma, with a tendency to form drop-like fluid cisternae, or ‘hydatids,’ that have conferred the designation of this class of diseases. Discrimination between degenerative and molar pregnancies can be difficult, and accurate subclassification as complete or partial mole directly impacts clinical prognosis and management.


Complete Hydatidiform Mole


Incidence


Epidemiologic studies have reported wide regional variation in the incidence of hydatidiform mole, of 0.57–1.6 per 1000 pregnancies in North America and Europe, rising to 2.0–8.5 in Asia, Africa, and Latin America. Although trophoblastic diseases occur more frequently in Asia than in North America or Europe, considerable difficulty exists in determining true incidence rates. Since these diseases are directly related to pregnancy, incidence ratios have been expressed per total number of pregnancies, number of deliveries, or live births in population-based or hospital-based studies. However, it is hard to obtain data regarding clinically unrecognized pregnancies, spontaneous and induced abortions, ectopic pregnancies, and uncomplicated live births and pregnancies that did not receive hospital-based care. Moreover, histopathologic examination of evacuated tissue is infrequent in some parts of the world and the diagnosis of hydatidiform mole can be missed, especially early in gestation.


Even in the high-incidence areas, overall incidence rates have significantly decreased over the last few decades with improved socioeconomic status of women, suggesting that environmental factors including dietary or nutritional factors are as important as ethnic or genetic factors. In the Netherlands, the incidence of trophoblastic disease increased significantly in recent years, partially explained by increased maternal age, increased proportion of live births of Asian descent, and improved diagnostic techniques.


Risk Factors


Extremes of maternal age and prior molar pregnancy are established risk factors. Conceptions occurring at extreme reproductive age, women over 45 and girls under 15, have higher risks of molar pregnancy than those for women aged 16–40.


Pathogenetic Mechanism


The genetic origin of hydatidiform moles was first suggested by the observation that about 90% have sex chromatin. Cytogenetic studies confirmed that about 90% of hydatidiform moles had a 46,XX karyotype and others triploid karyotypes. Based on the correlation of the histologic findings of hydatidiform moles and their karyotypes, existence of the two genetically distinct entities of complete and partial mole were suggested.


Most complete hydatidiform moles are a diploid androgenetic pregnancy in which all 46 chromosomes are paternally derived. Usually these arise following endoreduplication of a haploid sperm ( Figure 34.7 ), but a minor proportion result from fertilization of an anucleate egg by two sperms (dispermy) ( Figure 34.7 ). The fate of the missing maternal chromosomes is unclear, but may be caused by extrusion of both maternal sets of chromosomes into one of the polar bodies during meiosis, giving rise to an anucleate egg. Alternatively, retained maternal chromosomes may degenerate and thus fail to participate in postfertilization cell division. Triploid and tetraploid complete moles have been reported; however, these are still generally androgenetic in origin, having three or four paternal sets of chromosomes.




Figure 34.7


Genetic origins of hydatidiform moles. Endoreduplication of a haploid sperm or fertilization of two sperm in a functionally ‘empty’ ovum results in androgenetic complete hydatidiform mole (CHM). Fertilization of a normal ovum by two sperm results in triploid partial hydatidiform mole (PHM). Presence of biparental genome, but with mutation, results in biparental complete hydatidiform mole (BiCHM).


Rarely, complete moles are biparental diploid with both a maternal and paternal chromosome complement. This corroborates the suggestion that fertilization of an empty egg is not mandatory for the creation of a hydatidiform mole. Studies have shown that these biparental moles are frequently associated with patients with recurrent or familial molar disease. Biparental complete hydatidiform moles are now recognized as a clinically important subgroup, caused by maternal autosomal recessive mutation of NLRP7 , located in a 1.1 Mb region on chromosome 19q13.4. Mutation in this gene may result in dysregulation of imprinting in the female germ line with abnormal development of both embryonic and extraembryonic tissue.


Clinical Features


Molar pregnancies are now diagnosed at an earlier gestational age due to routine use of first trimester ultrasonography. Formerly, the majority of patients presented by 20 weeks of gestation with vaginal bleeding, symptomatic anemia, passage of molar tissue, excessive uterine size, hyperemesis, and markedly elevated hCG levels. Pre-eclampsia was observed in approximately 27%, and clinically evident hyperthyroidism in about 7% of the cases. Abdominal pain and pelvic pain resulting from enlarged theca lutein cysts of the ovary were commonly associated, and pelvic ultrasound examination revealed a characteristic ‘snowstorm appearance.’ Recently, however, the gestational age at the time of ultrasound diagnosis ranges from 5.0 to 12.5 weeks (median 8–9 weeks). Accordingly, the clinical presentation has changed considerably; excessive uterine size, anemia, hyperemesis, and metastatic disease are less common, and earlier stage molar tissues are submitted for examination. Today 40% of women are asymptomatic, and most symptomatic patients present with vaginal bleeding or suspected miscarriage in early pregnancy. In the first trimester, a significant proportion of complete moles demonstrate minimal ultrasound findings and are missed by this modality. Overall sensitivity for the ultrasound diagnosis of molar gestations is 40–60%.


Gross and Microscopic Findings


Pathologic findings of first trimester moles are more commonly encountered over the past decade due to the current practice of very early uterine evacuation. Thus, it is important for pathologists to recognize the subtle, but distinctive, histopathologic features unique to both early and late complete hydatidiform moles.


Grossly, the amount of tissue from early moles is less than that of advanced moles. The chorionic villi of early moles have smaller mean maximal villous diameter, and may not be grossly hydropic, unlike the more characteristically grape-like hydrops seen in late moles.


Microscopically, variable degrees of trophoblastic proliferation and hydropic change are identified in all complete moles, but the histopathologic presentation differs by gestational age.


Early (First Trimester) Complete Hydatidiform Moles


Early moles in which trophoblastic proliferation and hydropic change is minimal ( Figure 34.8 ) are easily confused with non-molar hydropic abortions. At this early phase, molar chorionic villi have bulbous outlines resembling blunt finger-like projections, and the villous stroma may not have appreciable hydropic change. Villous trophoblastic proliferation is minimal or is frequently proliferated in a polar fashion ( Figure 34.9 ), resembling polar proliferation of normal anchoring villi in early developing placentas. Trophoblastic pseudoinclusions, although often present, are not diagnostic, as they also may be seen in partial moles and aneuploid gestations. It is a combination of hypercellular basophilic stroma, immature blood vessels, and abnormal villous profiles that characterizes early complete moles, as these individual features may be seen separately and to a lesser extent in normal early developing placentas.




Figure 34.8


Early (first trimester) complete hydatidiform mole during the first trimester. Trophoblastic proliferation or hydropic change is nearly absent, which may cause underdiagnosis as non-molar hydropic abortion.



Figure 34.9


Early complete hydatidiform mole during the first trimester. Note the bulbous outlines of the chorionic villi and polar proliferation of villous trophoblast, resembling those of normal anchoring villi.


Poorly formed immature blood vessels in the villous stroma are characteristic of early moles. Vascular structures, when present ( Figure 34.10 ), are linear cords in basophilic stroma, similar to the angiogenic cell cords of normal placentas ( Figure 34.3A ). Rarely, there are cleft-like spaces within the vascular structures, but unlike normal placentas they almost never contain hematopoietic components or red blood cells. There is characteristic karyorrhexis and apoptosis of stromal cells and immature vascular structures, scattering karyorrhectic nuclear debris throughout the villous stroma ( Figure 34.11 ). Karyorrhexis and apoptosis within the villous stroma of non-molar hydropic abortuses and normal placentas are limited to a few cells within small terminal villi.




Figure 34.10


Early complete hydatidiform mole during the first trimester. Immature vascular structure with apoptotic nuclear debris in basophilic stroma is a characteristic feature of early moles.



Figure 34.11


Early complete hydatidiform mole, first trimester. Markedly increased apoptosis in the stromal cells as well as in the immature blood vessels is a frequent feature of early moles.


Advanced (Second Trimester) Complete Hydatidiform Moles


The cellular and mildly edematous basophilic stroma of early moles progressively changes to form hydropic villi with central acellular cisternae, and eventually, diffusely hydropic hypocellular villi ( Figure 34.12A–C ). Stroma is progressively displaced from the central part of the villi by accumulated fluid. These hydropic vesicles have grossly visible ‘bunch of grapes’ appearance filling the entire uterine cavity ( Figure 34.13 ). Circumferential proliferation of cytotrophoblast, intermediate trophoblast, and syncytiotrophoblast is prominent ( Figures 34.14 and 34.15 ), sometimes forming large sheets of trophoblast around the edematous villi. The trophoblast of complete moles has variable degrees of cytologic atypia, which may include nuclear pleomorphism and heterochromasia, often accompanied by cytoplasmic vacuoles ( Figure 34.16 ). The vacuoles are relatively more prominent than seen in normal trophoblast at the same gestational age. The degree of trophoblastic proliferation and hydropic change appears to be a time-dependent phenomenon that varies by gestational age, and is not related to the risk of subsequent persistent trophoblastic neoplasia.




Figure 34.12


Progressive hydropic changes in the villous stroma of complete hydatidiform mole shown by blood vessel (CD31) immuno­stain. Numerous brown staining immature blood vessels are present in the cellular nonhydropic stroma during the first trimester (A) , soon to be displaced. A cisterna is formed by accumulation of fluid in the center of the cellular nonhydropic stroma (B) . In the second trimester, avascular hydropic villi are formed by extensive accumulation of vesicular fluid in vesicular cisternae (C) .







Figure 34.13


Complete hydatidiform mole in the second trimester of pregnancy. Molar tissue has a grossly visible ‘bunch of grapes’ appearance filling the entire uterine cavity



Figure 34.14


Complete hydatidiform mole in the second trimester of pregnancy. Circumferential trophoblastic proliferation and hydropic change of villous stroma are evident.



Figure 34.15


Complete hydatidiform mole in the second trimester of pregnancy. Proliferating trophoblast are composed of cytotropho­blast, intermediate trophoblast, and syncytiotrophoblast.



Figure 34.16


Complete hydatidiform mole in the second trimester of pregnancy. The trophoblast has variable degrees of cytologic atypia and frequent cytoplasmic vacuoles, although vacuoles themselves are not a diagnostic feature.


Molar implantation sites are almost always exaggerated, in that intermediate trophoblastic cells are more atypical and the Ki-67 labeling index is higher than for a normal pregnancy. Biparental, triploid, or tetraploid complete moles and 46,XX and 46,XY complete moles are histologically and immunohistochemically indistinguishable from the more common androgenetic diploid mole.


Differential Diagnosis and Special Studies


Complete hydatidiform moles can be, and usually are, diagnosed based on the histopathologic findings alone using the above-described criteria. However, significant interobserver and intraobserver variability is observed, especially during early pregnancy. Distinction of molar from non-molar pregnancy and subclassification of moles into complete and partial types is important because subsequent management and the risk of persistent disease are different. Formerly, diagnostic difficulty was most frequently observed between complete and partial moles, but distinguishing complete moles from non-molar hydropic abortion is more problematic these days because most of the placental tissues are evacuated in the first trimester.


Introduction of immunostaining for p57 kip2 (CDKN1C), a paternally imprinted biomarker expressed only from the maternal genome of villous trophoblast, permits distinction between androgenetic (complete mole) and biparental (normal placenta, hydropic abortion, partial mole) tissues. Lack of p57 kip2 immunohistochemical staining is thus a clinically useful feature of complete moles, contrasting with positive expression in all biparental gestations. Interpretation should be based solely on scoring of the villous cytotropho­blast as extravillous trophoblast relax the imprint and thus may demonstrate variable expression even in androgenetic cells ( Figure 34.17A–C ).




Figure 34.17


p57 kip2 immunostaining patterns in complete and partial hydatidiform moles, and hydropic abortion (A–C) . Immuno­negativity for p57 kip2 in the villous stromal cells and villous cytotrophoblastic cells of complete hydatidiform mole (A) is contrasted with the immunopositivities in those cell components in partial hydatidiform mole (B) and non-molar abortion (C) . Diagnostic intrepretation should be based on villous surface trophoblast only, as solid columns of extravillous trophoblast emerging from the villous tips maintain p57 staining even in complete moles (A).






If both histologic features and the p57 kip2 result are equivocal, DNA ploidy analysis by flow cytometry or image analysis and chromosomal enumeration by fluorescent or chromogenic in situ hybridization ( Figure 34.18A and B ) are of great value in making the distinction between a diploid complete ( Figure 34.18A ) and triploid partial hydatidiform mole ( Figure 34.18B ). Even with those ancillary studies, diagnosis of hydatidiform mole can sometimes be difficult. Recently, DNA genotyping has been used to confirm their unique parental chromosomal compositions of complete and partial hydatidiform moles except for rare biparental complete moles and complete moles arising from a twin gestation. However, decidual tissue should be carefully removed during the preparation.




Figure 34.18


Chromogenic in situ hybridization using a centromere probe. Complete hydatidiform mole shows less than two signals in most of the cells (A) , whereas a significant number of cytotrophoblast and villous stromal cells demonstrate three signals in partial hydatidiform mole (B) . Although trisomy and triploid status cannot be distinguished, it is a simple and useful method to confirm the diagnosis of partial mole in conjunction with histologic features.




Hydropic non-molar abortion is often histologically difficult to differentiate from early complete mole because of hydropic stroma. Mature blood vessels containing hemato­poietic components, if present, are a helpful feature for the exclusion of mole. However, hydropic abortuses in early pregnancy may lack mature vascular structures. In hydropic abortuses, trophoblastic cells lining the chorionic villi are frequently stretched and thin, and the villous outline is usually smooth and rounded ( Figure 34.19 ). Although significant hydropic change is observed in hydropic abortion, central cisterna formation is less frequent, and extensive stromal karyorrhexis is rare. If the tissue is well preserved the diagnosis can easily be resolved with p57 kip2 immunostaining.




Figure 34.19


Non-molar hydropic abortion. The villous stroma has an edematous and myxoid appearance, but stromal blood vessels are well formed. The trophoblastic layer is thin, and the villous outline is usually smooth and rounded.


Nonhydropic normal early gestations may also be confused with complete moles because of prominent and confluent trophoblast along the external circumference of the chorionic villi ( Figure 34.4 ). Mature stromal blood vessels containing distinct lumens and hematopoietic components, if present, and immunopositivity for p57 kip2 antibody are helpful features for the exclusion of complete moles.


Although hydatidiform moles, either complete or partial, do occur in ectopic sites, molar pregnancies in ectopic locations should be diagnosed using strict histologic criteria. Non-molar ectopic gestations typically present early, when sheets of particularly prominent extravillous trophoblast and degenerative hydropic changes can easily be mistaken for molar disease ( Figure 34.20 ). When the diagnosis is equivocal, positive immunohistochemical staining for p57 kip2 will exclude complete mole.




Figure 34.20


Ectopic tubal pregnancy. Exuberant trophoblastic proliferation in the early gestational period may cause misdiagnosis of tubal pregnancy as a hydatidiform mole in an ectopic site.


Treatment and Prognostic Factors


Once molar pregnancy is suspected by clinical history, physical examination, serum β-hCG level, or ultrasonographic findings, diagnostic tissue is obtained by dilatation and curettage and clinical course monitored by biochemical (hCG) follow-up. Since molar pregnancies are very vascular and commonly invade the myometrium, suction curettage is recommended to minimize the risk of uterine perforation. Non-metastatic complete hydatidiform mole can be successfully treated with preservation of fertility in approximately 80% of patients.


Partial Hydatidiform Mole


Partial hydatidiform mole is defined as a conceptus with a fetus (alive or dead) and a single placenta with focal hydatidiform change of the villi in the presence of trophoblastic hyperplasia. Although an embryo or fetus often can be demonstrated, sometimes this is not represented in the available specimen, either because of sampling error or prior passage or degeneration of fetal parts.


There is continuing uncertainty regarding the frequency and natural history of partial moles because of difficulty of histopathologic diagnosis, and variable access to ploidy and molecular genetic analysis.


Pathogenetic Mechanism


Partial moles differ from complete moles in that they are almost always triploid, having a 69,XXX, 69,XXY, or 69,XYY karyotype. In almost all cases, the additional chromosome set is paternally derived, or diandric. The most common mechanism is fertilization of an ovum by a diploid sperm or by two haploid sperm ( Figure 34.7 ). However, only a portion of paternally derived triploid (diandric triploidy) placentas develop partial molar phenotype, indicating that the mere presence of two paternal haploid genomes is insufficient for molar development. Additionally, non-molar maternally derived triploidy (digynic triploids) may be accompanied by degenerative hydropic change but lack other histologic features of partial moles. Sometimes, a triploid placenta is associated with a grossly visible fetus, but most are digynic and thus not a partial mole or confined placental mosaicism with a diploid fetus. Thus, in the absence of pathognomonic histologic features, triploidy alone is not diagnostic of partial mole. This is especially the case with first trimester spontaneous abortions having degenerative hydropic change, as non-molar digynic triploidy is the most common form of triploidy in this subset of conceptuses. Occasionally, trisomies 2, 7, 15, 16, and 22 may share some features with partial mole, such as villous hydrops and trophoblastic proliferation. Tetraploid partial moles have also been reported and they usually have an excess of paternal genomes.


Clinical Features


Symptoms and signs of patients with partial moles are not different from those of complete moles. Vaginal bleeding is the main presenting symptom. The main clinical diagnosis is threatened or incomplete abortion. They tend to have much less uterine enlargement and relatively lower concentration of hCG than those of complete moles. Patients with partial mole also have a risk of pre-eclampsia and hyperthyroidism. Hydropic change in partial moles is minimal in the first trimester of pregnancy, becoming prominent only in the second or third trimester. Therefore, most first trimester partial moles escape detection by ultrasound or macroscopic examination, and when encountered are difficult to distinguish from more common digynic triploid spontaneous abortions. Intraplacental choriocarcinoma directly arising from triploid partial molar gestations has been described.


Gross and Microscopic Findings


Partial moles may or may not have grossly recognizable hydropic villi. The size of hydropic villi is usually smaller than that of complete moles, ranging from 1.2 to 6.5 mm.


Microscopically, partial mole is characterized by variably sized hydropic or fibrotic villi, mild to moderate tropho­blastic hyperplasia, and irregular villous contour with or without trophoblastic inclusions ( Figure 34.21 ). They tend to have considerably less trophoblastic proliferation than complete moles. Angulated irregular villous outline frequently produces trophoblastic nests or islands within the stroma, which is called ‘trophoblastic inclusion,’ but it is by no means a diagnostic feature. In contrast to complete moles, the stromal blood vessels may contain fetal hemato­poietic elements or nucleated red blood cells. Central cisternae are consistently identified, and frequently have a characteristic maze-like angiomatoid pattern in the stroma ( Figure 34.22 ). The villous stroma often has extensive stromal fibrosis, which is prominent especially in the later gestational period. Accurate diagnosis of partial moles in the first trimester remains a challenge, as characteristic features are not yet sufficiently developed to reliably distinguish them from hydropic abortion.




Figure 34.21


Triploid partial hydatidiform mole. It is characterized by variably sized hydropic or fibrotic villi, irregular villous contour with trophoblastic inclusions, and minimal trophoblastic proliferation.



Figure 34.22


Triploid partial hydatidiform mole. This triploid, first trimester mole has a well-formed maze-like angiomatoid cisterna.


Immunostaining for p57 kip2 shows diffuse expression in all cellular components including cytotrophoblast and villous stromal cells, but is noncontributory in the differential diagnosis of partial mole from degenerated spontaneous abortion.


Differential Diagnosis


There is significant interobserver and intraobserver variability in the histologic diagnosis of partial moles, even among placental pathologists. There can be confusion in the application of diagnostic criteria, which has led to both overdiagnosis of hydropic abortuses and underdiagnosis of complete moles. Frequently, differential diagnosis between partial mole and non-molar hydropic abortion is difficult. Immunostaining for p57 kip2 is not helpful in those cases, and trophoblastic hyperplasia is an essential feature for the diagnosis of partial mole. Confirmatory evidence can be obtained by DNA ploidy analysis, chromosomal enumeration by fluorescent or chromogenic in situ hybridization, and DNA genotyping. In general, diploid gestations are not partial moles, but triploid conceptuses can be either diandric partial moles or digynic spontaneous abortions. Therefore, triploidy is an expected, but nonspecific, feature of the partial mole.


Twin pregnancy with a complete mole and normal conceptus should also be differentiated from partial mole because both conditions have an embryo, amniotic membrane, and admixed populations of hydropic and non­hydropic chorionic villi. Microscopic findings will be discussed in more detail in the following sections.


Placental mesenchymal dysplasia is a rare condition of placental vascular malformation that should be differentiated from partial mole. Antenatal ultrasonographic examination shows multiple cysts with anechoic regions. Clinically, it can be associated with slightly elevated levels of serum β-hCG. Grossly, there are grape-like vesicles in the parenchyma, which mimics molar pregnancy ( Figure 34.23 ). Microscopic findings are characterized by placentomegaly, multicystic placenta, and large edematous stem villi interspersed with normal villi ( Figure 34.24 ). Many have loose hydropic stem villi with myxoid stroma, rich in hyaluronic acid, cisterna formation, and chorangiomatoid change, but others have a fibromatous core ( Figure 34.25 ). Extravillous (intermediate) trophoblast can be prominent in the intervillous spaces. However, irregular villous outline with trophoblastic pseudo­inclusions, which is a diagnostic feature of partial mole, is not observed. Stem villi are mainly involved by the hydropic change in mesenchymal dysplasia, while terminal villi are mostly affected in partial moles.




Figure 34.23


Placental mesenchymal dysplasia. Cut surface of the placenta shows multiple grossly visible cysts in otherwise normal placental parenchyma.



Figure 34.24


Placental mesenchymal dysplasia. Dilated hydropic stem villi are interspersed within normal villi, mimicking partial hydatidiform mole.



Figure 34.25


Placental mesenchymal dysplasia. Characteristic features of partial hydatidiform mole including trophoblastic proliferation or inclusion are not seen.


Aneuploid placenta or placenta with structural chromosomal abnormalities including trisomy may show prominent scalloping of villous outlines, which may produce many intravillous trophoblastic pseudoinclusions. Microscopic findings are similar to those of partial mole, but trophoblastic proliferation is not identified ( Figure 34.26 ).




Figure 34.26


Aneuploid placenta from trisomy. Prominent scalloping of villous outlines with frequent intravillous trophoblastic pseudo­inclusions mimic those of partial hydatidiform mole, but trophoblastic proliferation is not identified.


Twin pregnancies with one complete mole and one normal gestation are rare, but when they occur, they can be confused with partial mole. The existence of such cases was proven by DNA polymorphism studies demonstrating sole paternal origin of the molar tissues and biparental origin of the normal gestation. The mortality rate for the coexistent twin fetus is high, usually attributed to spontaneous abortion or early pregnancy termination due to severe pre-eclampsia or vaginal bleeding, but the chances of a live birth have also been estimated as 21–40%. There is a 20–55% risk of persistent trophoblastic disease after twin pregnancy with complete mole, which is similar to or higher than that after a complete mole alone. Microscopically, two different populations of chorionic villi are identified in a well-sampled single specimen ( Figure 34.27A–E ). In cases of twin pregnancy composed of complete mole and normal gestation, the histologically different populations of villi are usually not intimately admixed, but separated ( Figure 34.27A ). Histologic findings vary with gestational age. Immunostaining for p57 kip2 will show different staining patterns between molar and non-molar villi.




Figure 34.27


Twin pregnancy with complete hydatidiform mole and coexisting normal pregnancy. (A) There are two separate and distinct populations of chorionic villi from normal placenta (open arrows) and complete hydatidiform mole (closed arrows). (B, C) Chorionic villi in normal placenta show well-formed blood vessels in the stroma (B) and expression of p57 kip2 in the cytotrophoblast and stromal cells (C) . (D, E) Complete hydatidiform mole shows central cisternae, immature blood vessels within cellular stroma at the periphery (D) , and immunonegativity for p57 kip2 (E) .










Treatment and Prognosis


Because of ambiguities in diagnosis, and lack of standardized outcome measures, there is disagreement regarding treatment of partial moles. Some have questioned whether women with partial moles need any β-hCG follow-up. However, approximately 0.2% to 4% of partial moles are followed by recurrent molar pregnancies, which is a significantly higher incidence than in women having a normal pregnancy. Rarely, histologically verified invasive mole, choriocarcinoma, or metastatic disease requiring chemotherapy have been described. All patients with molar gestations should be followed irrespective of type, although the absolute risk of persistent trophoblastic neoplasia is much lower for partial than for complete mole. There is no universally accepted protocol for β-hCG surveillance following evacuation of partial mole, as these have varied in both sampling frequency and recommended follow-up interval.


Recurrent partial mole is a very rare clinical disorder, but a second molar pregnancy occurs in 1.7%, of which two-thirds are partial and one-third complete.


Adverse Clinical Outcomes in Molar Disease


Persistent Trophoblastic Disease


The terms persistent trophoblastic disease and posthydatidiform gestational trophoblast neoplasia have been used interchangeably to indicate persistent mole, invasive mole, and choriocarcinoma. The reported frequency of persistent trophoblastic disease is 15–20% in complete and 0.2–4% in partial hydatidiform mole. When a patient has persistent trophoblastic disease by defined criteria ( Table 34.3 ) immediate work-up and treatment are indicated. Treatment should be individualized according to the prognostic factors and clinical stage.



Table 34.3

Criteria for the Diagnosis of Post-Hydatidiform Mole Trophoblastic Neoplasia







  • 1.

    Plateau of β-hCG lasts for four measurements over a period of 3 weeks or longer (days 1, 7, 14, and 21)


  • 2.

    A rise of β-hCG of 10% or greater on 3 consecutive weekly measurements over at least 2 weeks (days 1, 7, and 14)


  • 3.

    The presence of histologic choriocarcinoma


  • 4.

    Persistence of β-hCG 6 months after molar evacuation



Over the years various anatomic, clinical, and prognostic scoring systems have been used. The response to treatment with chemotherapy, surgery, and radiotherapy is influenced by several clinical factors that form the basis of the World Health Organization (WHO) scoring system. On the other hand, pure anatomic staging systems have not been universally adopted because the prognosis of patients in the same anatomic stage varies greatly and is affected by a number of clinical features.


In 2002, the International Federation of Obstetrics and Gynecology (FIGO) ratified a revised classification system for trophoblastic disease, which combines anatomic staging (pre-2002 FIGO) with clinical risk factors (WHO clinical score). A patient’s anatomic stage is first summarized by Roman numeral as I, II, III, or IV ( Table 34.4 ). This is then separated by a colon from the sum of all the clinical risk factor scores, expressed in Arabic numerals ( Table 34.5 ), e.g., stage II:4, stage IV:9. For purposes of reporting, patients with persistent trophoblastic disease are divided into high-risk and low-risk groups. Those with non-metastatic (stage I) and low-risk metastatic disease (stage II or III, metastases to lung and/or vagina) with total clinical score <7 can be treated with single agent chemotherapy: metho­trexate with or without folinic acid or actinomycin. Patients with high-risk metastatic gestational trophoblastic neoplasia (stage IV, clinical score ≥7) need intensive chemotherapy with multiple combination chemotherapy. Relapse after first-line chemotherapy for high-risk disease can often be treated by platinum-containing chemotherapy regimens. Almost 100% cure rate can be achieved in the majority of patients with optimal treatment.



Table 34.4

FIGO (2002) Anatomical Staging System















Stage I Disease confined to the uterus
Stage II GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament)
Stage III GTN extends to the lungs, with or without known genital tract involvement
Stage IV All other metastatic sites


Table 34.5

FIGO (2002) Clinical Risk Factor Score


























































Scores 0 1 2 4
Age <40 ≥40
Antecedent pregnancy Mole Abortion Term
Interval months from index pregnancy <4 4 to <7 7 to <13 ≥13
Pretreatment serum hCG (IU/ml) <10 3 10 3 to <10 4 10 4 to <10 5 ≥10 5
Largest tumor size (including uterus) 3 to <5 cm ≥5 cm
Site of metastases Lung Spleen, kidney Gastrointestinal Liver, brain
Number of metastases 1–4 5–8 >8
Previous failed chemotherapy Single drug Two or more drugs


Recurrent Hydatidiform Mole


Molar recurrence should be distinguished from persistence, and the risk in sporadic cases ranges from 1% to 4.3%. Women who have experienced one molar pregnancy have a 20-fold increased risk of a further molar pregnancy in comparison with other women in the general population. Second molar pregnancies are of the same type (complete vs partial) as the first in approximately three-quarters of cases. Multiple occurrences may be sporadic or familial. After two molar pregnancies, the risk of developing molar disease in a subsequent conception rises to 15–20%. The frequency of familial recurrent hydatidiform mole is not known, but more than 40 different familial cases, in which two or more individuals have molar pregnancies, have been reported in the English literature.


Invasive Mole


Invasive mole is defined as molar villi invading into the myometrium, cervical stroma, and blood vessels or metastasizing to an extrauterine site. The most common sites of metastasis are lung, liver, brain, vagina, and vulva. Rarely spinal cord and urinary bladder have been described. The diagnosis is usually made on a hysterectomy specimen. Since both invasive mole and choriocarcinoma have an elevated β-hCG titer and may produce metastatic lesions, these are often indistinguishable clinically when biopsied tissue only contains a scanty amount of atypical trophoblast without intact villi. According to FIGO 2000 criteria, patients with plateaued or rising consecutive β-hCG titers following molar evacuation are clinically classified as having persistent gestational trophoblastic disease and treated with chemotherapy irrespective of anatomic documentation of invasion or metastasis.


Initial presentation as an invasive mole is rare; rather, it is preceded by complete or partial mole in 75% and 18.5% of cases, respectively. Bleeding is the main cause of morbidity and mortality in patients with invasive or metastatic moles. Grossly, molar vesicles are usually identified in myometrium of hysterectomy specimens ( Figure 34.28 ). Microscopically, invasive and metastatic villi are similar in appearance to those of noninvasive moles, except they can be identified within myometrium, blood vessels, or distant tissues ( Figure 34.29 ). Adjacent myometrium around the invasive villi usually contains florid proliferation of extravillous trophoblasts, which are reminiscent of placental site trophoblastic tumor.




Figure 34.28


Invasive mole. Hydropic villi invade the entire myometrium.



Figure 34.29


Invasive mole. Molar villi within the myometrium show circumferential trophoblastic proliferation.


Treatment of Invasive Mole


Patients with invasive mole have a good prognosis. Even if disease has spread, single agent chemotherapy might be sufficient as long as the diagnosis is histologically confirmed. Approximately 80% of young patients treated with chemotherapy alone conceive after recovery. If untreated, invasive mole can result in uterine rupture or heavy bleeding. Metastatic lesions can successfully be treated by minimally invasive angiographic embolization.


Differential Diagnosis of Invasive Mole


Metastatic invasive mole needs to be differentiated from displacement of normal placental elements into the lung, known as trophoblastic pulmonary embolization, or villo­trophoblastic nodule. Most cases have been identified during postmortem examination performed in patients with sudden death in mid-gestation due to unrelated causes, but rare cases have been detected in asymptomatic patients. Careful examination of villous structure is useful in these cases, and immunopositivity for p57 kip2 in the cytotropho­blast lining chorionic villi is helpful to exclude invasive complete moles.




Complete Hydatidiform Mole


Incidence


Epidemiologic studies have reported wide regional variation in the incidence of hydatidiform mole, of 0.57–1.6 per 1000 pregnancies in North America and Europe, rising to 2.0–8.5 in Asia, Africa, and Latin America. Although trophoblastic diseases occur more frequently in Asia than in North America or Europe, considerable difficulty exists in determining true incidence rates. Since these diseases are directly related to pregnancy, incidence ratios have been expressed per total number of pregnancies, number of deliveries, or live births in population-based or hospital-based studies. However, it is hard to obtain data regarding clinically unrecognized pregnancies, spontaneous and induced abortions, ectopic pregnancies, and uncomplicated live births and pregnancies that did not receive hospital-based care. Moreover, histopathologic examination of evacuated tissue is infrequent in some parts of the world and the diagnosis of hydatidiform mole can be missed, especially early in gestation.


Even in the high-incidence areas, overall incidence rates have significantly decreased over the last few decades with improved socioeconomic status of women, suggesting that environmental factors including dietary or nutritional factors are as important as ethnic or genetic factors. In the Netherlands, the incidence of trophoblastic disease increased significantly in recent years, partially explained by increased maternal age, increased proportion of live births of Asian descent, and improved diagnostic techniques.


Risk Factors


Extremes of maternal age and prior molar pregnancy are established risk factors. Conceptions occurring at extreme reproductive age, women over 45 and girls under 15, have higher risks of molar pregnancy than those for women aged 16–40.


Pathogenetic Mechanism


The genetic origin of hydatidiform moles was first suggested by the observation that about 90% have sex chromatin. Cytogenetic studies confirmed that about 90% of hydatidiform moles had a 46,XX karyotype and others triploid karyotypes. Based on the correlation of the histologic findings of hydatidiform moles and their karyotypes, existence of the two genetically distinct entities of complete and partial mole were suggested.


Most complete hydatidiform moles are a diploid androgenetic pregnancy in which all 46 chromosomes are paternally derived. Usually these arise following endoreduplication of a haploid sperm ( Figure 34.7 ), but a minor proportion result from fertilization of an anucleate egg by two sperms (dispermy) ( Figure 34.7 ). The fate of the missing maternal chromosomes is unclear, but may be caused by extrusion of both maternal sets of chromosomes into one of the polar bodies during meiosis, giving rise to an anucleate egg. Alternatively, retained maternal chromosomes may degenerate and thus fail to participate in postfertilization cell division. Triploid and tetraploid complete moles have been reported; however, these are still generally androgenetic in origin, having three or four paternal sets of chromosomes.




Figure 34.7


Genetic origins of hydatidiform moles. Endoreduplication of a haploid sperm or fertilization of two sperm in a functionally ‘empty’ ovum results in androgenetic complete hydatidiform mole (CHM). Fertilization of a normal ovum by two sperm results in triploid partial hydatidiform mole (PHM). Presence of biparental genome, but with mutation, results in biparental complete hydatidiform mole (BiCHM).


Rarely, complete moles are biparental diploid with both a maternal and paternal chromosome complement. This corroborates the suggestion that fertilization of an empty egg is not mandatory for the creation of a hydatidiform mole. Studies have shown that these biparental moles are frequently associated with patients with recurrent or familial molar disease. Biparental complete hydatidiform moles are now recognized as a clinically important subgroup, caused by maternal autosomal recessive mutation of NLRP7 , located in a 1.1 Mb region on chromosome 19q13.4. Mutation in this gene may result in dysregulation of imprinting in the female germ line with abnormal development of both embryonic and extraembryonic tissue.


Clinical Features


Molar pregnancies are now diagnosed at an earlier gestational age due to routine use of first trimester ultrasonography. Formerly, the majority of patients presented by 20 weeks of gestation with vaginal bleeding, symptomatic anemia, passage of molar tissue, excessive uterine size, hyperemesis, and markedly elevated hCG levels. Pre-eclampsia was observed in approximately 27%, and clinically evident hyperthyroidism in about 7% of the cases. Abdominal pain and pelvic pain resulting from enlarged theca lutein cysts of the ovary were commonly associated, and pelvic ultrasound examination revealed a characteristic ‘snowstorm appearance.’ Recently, however, the gestational age at the time of ultrasound diagnosis ranges from 5.0 to 12.5 weeks (median 8–9 weeks). Accordingly, the clinical presentation has changed considerably; excessive uterine size, anemia, hyperemesis, and metastatic disease are less common, and earlier stage molar tissues are submitted for examination. Today 40% of women are asymptomatic, and most symptomatic patients present with vaginal bleeding or suspected miscarriage in early pregnancy. In the first trimester, a significant proportion of complete moles demonstrate minimal ultrasound findings and are missed by this modality. Overall sensitivity for the ultrasound diagnosis of molar gestations is 40–60%.


Gross and Microscopic Findings


Pathologic findings of first trimester moles are more commonly encountered over the past decade due to the current practice of very early uterine evacuation. Thus, it is important for pathologists to recognize the subtle, but distinctive, histopathologic features unique to both early and late complete hydatidiform moles.


Grossly, the amount of tissue from early moles is less than that of advanced moles. The chorionic villi of early moles have smaller mean maximal villous diameter, and may not be grossly hydropic, unlike the more characteristically grape-like hydrops seen in late moles.


Microscopically, variable degrees of trophoblastic proliferation and hydropic change are identified in all complete moles, but the histopathologic presentation differs by gestational age.




Incidence


Epidemiologic studies have reported wide regional variation in the incidence of hydatidiform mole, of 0.57–1.6 per 1000 pregnancies in North America and Europe, rising to 2.0–8.5 in Asia, Africa, and Latin America. Although trophoblastic diseases occur more frequently in Asia than in North America or Europe, considerable difficulty exists in determining true incidence rates. Since these diseases are directly related to pregnancy, incidence ratios have been expressed per total number of pregnancies, number of deliveries, or live births in population-based or hospital-based studies. However, it is hard to obtain data regarding clinically unrecognized pregnancies, spontaneous and induced abortions, ectopic pregnancies, and uncomplicated live births and pregnancies that did not receive hospital-based care. Moreover, histopathologic examination of evacuated tissue is infrequent in some parts of the world and the diagnosis of hydatidiform mole can be missed, especially early in gestation.


Even in the high-incidence areas, overall incidence rates have significantly decreased over the last few decades with improved socioeconomic status of women, suggesting that environmental factors including dietary or nutritional factors are as important as ethnic or genetic factors. In the Netherlands, the incidence of trophoblastic disease increased significantly in recent years, partially explained by increased maternal age, increased proportion of live births of Asian descent, and improved diagnostic techniques.




Risk Factors


Extremes of maternal age and prior molar pregnancy are established risk factors. Conceptions occurring at extreme reproductive age, women over 45 and girls under 15, have higher risks of molar pregnancy than those for women aged 16–40.




Pathogenetic Mechanism


The genetic origin of hydatidiform moles was first suggested by the observation that about 90% have sex chromatin. Cytogenetic studies confirmed that about 90% of hydatidiform moles had a 46,XX karyotype and others triploid karyotypes. Based on the correlation of the histologic findings of hydatidiform moles and their karyotypes, existence of the two genetically distinct entities of complete and partial mole were suggested.


Most complete hydatidiform moles are a diploid androgenetic pregnancy in which all 46 chromosomes are paternally derived. Usually these arise following endoreduplication of a haploid sperm ( Figure 34.7 ), but a minor proportion result from fertilization of an anucleate egg by two sperms (dispermy) ( Figure 34.7 ). The fate of the missing maternal chromosomes is unclear, but may be caused by extrusion of both maternal sets of chromosomes into one of the polar bodies during meiosis, giving rise to an anucleate egg. Alternatively, retained maternal chromosomes may degenerate and thus fail to participate in postfertilization cell division. Triploid and tetraploid complete moles have been reported; however, these are still generally androgenetic in origin, having three or four paternal sets of chromosomes.




Figure 34.7


Genetic origins of hydatidiform moles. Endoreduplication of a haploid sperm or fertilization of two sperm in a functionally ‘empty’ ovum results in androgenetic complete hydatidiform mole (CHM). Fertilization of a normal ovum by two sperm results in triploid partial hydatidiform mole (PHM). Presence of biparental genome, but with mutation, results in biparental complete hydatidiform mole (BiCHM).


Rarely, complete moles are biparental diploid with both a maternal and paternal chromosome complement. This corroborates the suggestion that fertilization of an empty egg is not mandatory for the creation of a hydatidiform mole. Studies have shown that these biparental moles are frequently associated with patients with recurrent or familial molar disease. Biparental complete hydatidiform moles are now recognized as a clinically important subgroup, caused by maternal autosomal recessive mutation of NLRP7 , located in a 1.1 Mb region on chromosome 19q13.4. Mutation in this gene may result in dysregulation of imprinting in the female germ line with abnormal development of both embryonic and extraembryonic tissue.




Clinical Features


Molar pregnancies are now diagnosed at an earlier gestational age due to routine use of first trimester ultrasonography. Formerly, the majority of patients presented by 20 weeks of gestation with vaginal bleeding, symptomatic anemia, passage of molar tissue, excessive uterine size, hyperemesis, and markedly elevated hCG levels. Pre-eclampsia was observed in approximately 27%, and clinically evident hyperthyroidism in about 7% of the cases. Abdominal pain and pelvic pain resulting from enlarged theca lutein cysts of the ovary were commonly associated, and pelvic ultrasound examination revealed a characteristic ‘snowstorm appearance.’ Recently, however, the gestational age at the time of ultrasound diagnosis ranges from 5.0 to 12.5 weeks (median 8–9 weeks). Accordingly, the clinical presentation has changed considerably; excessive uterine size, anemia, hyperemesis, and metastatic disease are less common, and earlier stage molar tissues are submitted for examination. Today 40% of women are asymptomatic, and most symptomatic patients present with vaginal bleeding or suspected miscarriage in early pregnancy. In the first trimester, a significant proportion of complete moles demonstrate minimal ultrasound findings and are missed by this modality. Overall sensitivity for the ultrasound diagnosis of molar gestations is 40–60%.




Gross and Microscopic Findings


Pathologic findings of first trimester moles are more commonly encountered over the past decade due to the current practice of very early uterine evacuation. Thus, it is important for pathologists to recognize the subtle, but distinctive, histopathologic features unique to both early and late complete hydatidiform moles.


Grossly, the amount of tissue from early moles is less than that of advanced moles. The chorionic villi of early moles have smaller mean maximal villous diameter, and may not be grossly hydropic, unlike the more characteristically grape-like hydrops seen in late moles.


Microscopically, variable degrees of trophoblastic proliferation and hydropic change are identified in all complete moles, but the histopathologic presentation differs by gestational age.




Early (First Trimester) Complete Hydatidiform Moles


Early moles in which trophoblastic proliferation and hydropic change is minimal ( Figure 34.8 ) are easily confused with non-molar hydropic abortions. At this early phase, molar chorionic villi have bulbous outlines resembling blunt finger-like projections, and the villous stroma may not have appreciable hydropic change. Villous trophoblastic proliferation is minimal or is frequently proliferated in a polar fashion ( Figure 34.9 ), resembling polar proliferation of normal anchoring villi in early developing placentas. Trophoblastic pseudoinclusions, although often present, are not diagnostic, as they also may be seen in partial moles and aneuploid gestations. It is a combination of hypercellular basophilic stroma, immature blood vessels, and abnormal villous profiles that characterizes early complete moles, as these individual features may be seen separately and to a lesser extent in normal early developing placentas.




Figure 34.8


Early (first trimester) complete hydatidiform mole during the first trimester. Trophoblastic proliferation or hydropic change is nearly absent, which may cause underdiagnosis as non-molar hydropic abortion.



Figure 34.9


Early complete hydatidiform mole during the first trimester. Note the bulbous outlines of the chorionic villi and polar proliferation of villous trophoblast, resembling those of normal anchoring villi.


Poorly formed immature blood vessels in the villous stroma are characteristic of early moles. Vascular structures, when present ( Figure 34.10 ), are linear cords in basophilic stroma, similar to the angiogenic cell cords of normal placentas ( Figure 34.3A ). Rarely, there are cleft-like spaces within the vascular structures, but unlike normal placentas they almost never contain hematopoietic components or red blood cells. There is characteristic karyorrhexis and apoptosis of stromal cells and immature vascular structures, scattering karyorrhectic nuclear debris throughout the villous stroma ( Figure 34.11 ). Karyorrhexis and apoptosis within the villous stroma of non-molar hydropic abortuses and normal placentas are limited to a few cells within small terminal villi.




Figure 34.10


Early complete hydatidiform mole during the first trimester. Immature vascular structure with apoptotic nuclear debris in basophilic stroma is a characteristic feature of early moles.



Figure 34.11


Early complete hydatidiform mole, first trimester. Markedly increased apoptosis in the stromal cells as well as in the immature blood vessels is a frequent feature of early moles.




Advanced (Second Trimester) Complete Hydatidiform Moles


The cellular and mildly edematous basophilic stroma of early moles progressively changes to form hydropic villi with central acellular cisternae, and eventually, diffusely hydropic hypocellular villi ( Figure 34.12A–C ). Stroma is progressively displaced from the central part of the villi by accumulated fluid. These hydropic vesicles have grossly visible ‘bunch of grapes’ appearance filling the entire uterine cavity ( Figure 34.13 ). Circumferential proliferation of cytotrophoblast, intermediate trophoblast, and syncytiotrophoblast is prominent ( Figures 34.14 and 34.15 ), sometimes forming large sheets of trophoblast around the edematous villi. The trophoblast of complete moles has variable degrees of cytologic atypia, which may include nuclear pleomorphism and heterochromasia, often accompanied by cytoplasmic vacuoles ( Figure 34.16 ). The vacuoles are relatively more prominent than seen in normal trophoblast at the same gestational age. The degree of trophoblastic proliferation and hydropic change appears to be a time-dependent phenomenon that varies by gestational age, and is not related to the risk of subsequent persistent trophoblastic neoplasia.


Oct 5, 2019 | Posted by in GYNECOLOGY | Comments Off on Gestational Trophoblastic Disease
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