Neoplasms
Choriocarcinoma
Placental site trophoblastic tumour
Epithelioid trophoblastic tumour
Molar pregnancies
Hydatidiform mole
• Complete
• Partial
• Invasive
Non-neoplastic lesions
Exaggerated placental site
Placental site nodule and plaque
Abnormal (nonmolar) villous lesions
The prevalence of hydatidiform mole varies by country, with the highest incidence in Southeast Asia (3.8–13/1000 pregnancies) and the lowest incidence in the USA and Europe (0.5–1.84/1000 pregnancies) [1–3]. In Japan, the incidence is decreasing from 2.5/1000 pregnancies in 1974 to 1.65/1000 pregnancies in 2000 [4].
Significant risk factors are maternal age >40 years, previous spontaneous abortion and previous history of hydatidiform mole, and Asian ethnicity and genetics. Some studies suggest that vitamin A deficiency and nutritional and socioeconomic factors may increase the risk of molar pregnancy [1, 3, 5].
Persistent GTD is determined by hCG values that have plateaued or are increasing after curettage for hydatidiform mole. Further clinical and imaging studies are indicated to exclude invasive mole or high-risk GTD including choriocarcinoma [5–7]. The incidences of persistent GTD are 15–29% following CM and 0–4% after PM [1, 6]. It is crucial to diagnostically separate the non-molar, hydropic abortions from hydatidiform moles for prognostic and clinical management purposes.
The clinical presentation of a CM has changed considerably over the past three decades. CM was once easily diagnosed in the second trimester, and certain symptoms were common at the time of presentation, including prominent uterine enlargement, anemia, toxemia, hyperemesis, hyperthyroidism, and respiratory failure. However, the diagnosis is now typically made in the first trimester often before classic clinical symptoms develop. This is based on the availability of accurate and sensitive tests for hCG and the widespread use of both transabdominal and transvaginal ultrasonographies [5, 6].
Although abortion specimens with hydropic chorionic villi are routinely encountered in general and gynecological pathology practice, the histological features of early CM (at less than 12-week gestational age), PM, and hydropic abortus often overlap and have a low sensitivity and specificity, especially for PM [8].
The development of ancillary diagnostic testing methods, including immunohistochemical detection of imprinted genes/products, DNA ploidy analysis, and, most recently, DNA short tandem repeat (STR) genotyping, has advanced the study of GTD during the past three decades [9–11]. Diagnostic algorisms have been proposed in pathological diagnosis of PTD with the concomitant use of traditional histopathological assessment and ancillary studies for higher diagnostic accuracy [9, 10].
Clinical and pathological diagnostic features of hydatidiform moles and non-molar hydropic abortus are summarized in Table 13.2.
Table 13.2
Diagnostic features of hydatidiform moles
Features | CM | ECM (6.5–12 weeks of gestation) | PM | Hydropic abortus |
|---|---|---|---|---|
Karyotype | 46XX, 46XY (paternal-only) | 46XX, 46XY (paternal-only) | 69XXX, 69XXY, 69XYY | 46XX, 46XY |
Pretreatment hCG (mIU/mL) | >100 × 103 | Normal or <100 × 103 | Normal or <100 × 103 | Normal |
Ultrasound | Snow storm pattern | – | Focal cystic change | – |
Gestational sac and fetus | Absence | Absence | Rarely presence | Presence |
Macroscopy | Overall hydropic change | No gross abnormality | Focal hydropic change | No gross abnormality |
Villous shape | ||||
Outline | Round to oval | Polypoid | Scalloped with pseudo-inclusionfjord-like invagination | Round to oval |
Cauliflower shapes | ||||
Crab-shaped | ||||
Enlargement | Marked | Normal size | Some enlarged, but often not prominent | Often marked |
Cistern | Prominent | Uncommon | Variable, usually not prominent | Variable, usually not prominent |
Trophoblastic hyperplasia | ||||
Extent | Multifocal | Circumferencial | Focal, syncytiotrophoblast knuckles (sprouts) | None |
Amount | Abundant | Increase | Minimal | None |
Atypia | Marked | Mild to moderate | Limited to mild | None |
Normal villi | None or few | Some | Numerous | Sometimes |
Apoptosis in villous stroma | Marked | Marked to mild | Rare | None |
Vasculature and nucleated RBCs | Absent, generally | Absent, capillary may be present | Common | Absent, generally |
p57 KIP2 immunostain in cytotrophoblast and villous stromal cells | Negative | Negative | Positive | Positive |
Persistent trophoblastic disease | 15–29% | 15–29% | 0–4% | 0% |
13.1.1 Compete Hydatidiform Mole
WHO classification (2014) defines CM as a nonneoplastic, proliferative disorder of the placenta, resulting in villous hydrops and trophoblastic hyperplasia without embryonic development and having androgenic diploid karyotype (diploid paternal-only genome) [1].
Clinical findings are vaginal bleeding in the second trimester, prominent uterine enlargement, and marked elevation of serum hCG (>100 × 103 mIU/mL). Ultrasonography shows the absence of fetus and “snow storm” pattern. These are characteristic features of well-developed, classic CM [6].
Genetically, the majority of CM cases have a diploid, paternal-only genome with the karyotypes of 46XX or 46XY. Two paternal haploid chromosome sets consist of either monosomic/homozygous (80–90%) or dispermic/heterozygous (10–20%) origin (Fig. 13.1) [1, 3]. Rarely, tetraploid CM may exist with four paternal haploid sets in the genome.
Fig. 13.1
Pathogenesis of complete hydatidiform mole and partial hydatidiform mole
Macroscopically, classic CM consists of bulky, bloody tissue with uniformly hydropic “grapelike” villi (Fig. 13.2) [1, 5, 6]. The edematous villi range from a few millimeters to over 10 mm in diameter. Fetal and normal placenta are absent apart from rare exceptions [12, 13]. Early complete mole (ECM) of 6.5 to 12 weeks of gestational age is typically normal grossly [6].
Fig. 13.2
Gross appearance of complete hydatidiform mole presenting diffuse grapelike villous swelling
Histological features of classic CM differ from those of ECM. Knowledge of the gestational age is useful in determining the appropriate histological criteria to be applied. Classic CM presents with diffuse villous enlargement and edema, frequent cistern formation, and conspicuous trophoblastic hyperplasia. Cistern formation is cavitation in the center of the villi produced by necrosis of the mesenchyme (Fig. 13.3a). Villous stromal vessels are usually absent. The villi are usually round to oval. Trophoblastic hyperplasia is circumferential, and significant cytological atypia of all three trophoblasts is almost always present (Fig. 13.3b). Mitotic figures are usually found. There are no fetal tissue and normal placental structures excluding very rare exceptions. In contrast, ECM shows minimal hydropic change and cistern formation is rare [14, 15]. The villi have irregular shapes called polypoid, cauliflower-like, or crab-shaped (Fig. 13.3c). Trophoblastic hyperplasia is mild to moderate in degree, and trophoblast shows circumferential or random distribution on the villi. An exaggerated placental site (molar implantation site) with atypical trophoblast is often present. The villous stroma is abnormally cellular with prominent apoptosis (karyorrhexis) and myxoid change (Fig. 13.3d) [14, 15]. Capillary vessels can be seen in the stroma with or without nucleated red blood cells. Stromal fibrosis is absent.
Fig. 13.3
Histological appearance of complete hydatidiform mole. (a) Swollen villi with necrosis of the mesenchyme produce cistern (*), and left lower side villi show polypoid, crab-shaped irregular outline. (b) The implantation site trophoblast presenting conspicuous trophoblastic atypia. (c) Early complete hydatidiform mole. Characteristic irregular villous contour resembling cauliflower-like shape. (d) Early complete hydatidiform mole. Hypercellular myxoid villous stroma with karyorrhexis (apoptosis) accompanied by modest circumferential trophoblastic proliferation
The prevalence of persistent gestational trophoblastic disease is 15–29%, and 2–3% of the patients develop choriocarcinoma after CM [1, 3, 6]. The risk of subsequent CM is 1–1.8% and 10–18% after two consecutive CMs [16, 17]. The rare case of recurrent, familial, and biparental CM develops as a result of abnormal imprinting and overexpression of the paternal genome related to maternal mutation of NALP7/NLRP7 and more rarely KHDC3L [3, 18].
13.1.2 Partial Hydatidiform Mole (PM) (Figs. 13.5, 13.6 and 13.7a–d)
PM is defined as a hydatidiform mole with a spectrum of villous populations ranging from normal size to substantial hydrops with mild, focal trophoblastic hyperplasia. Most cases present diandric-monogynic triploid genome [1, 3, 5, 6, 19].
Clinical presentations are vaginal bleeding, missed or incomplete abortion in the late first or early second trimester, normal to mild elevated serum hCG (<100 × 103 mIU/mL), and a focal cystic change in the placenta on ultrasound. Fetal tissues or gestational sac can be seen [19].
Genetically, PM has a triploid diandric-monogynic genome with karyotype of 69XXY (70%), 69XXX (27%), and 69XYY (3%) (Fig. 13.1) [1, 3, 19].
Grossly, hydropic vesicles admixed with normal placental tissue are characteristic features (Fig. 13.4). Gestational sac, abnormal fetus, and normal fetus might be found.
Fig. 13.4
Gross appearance of partial hydatidiform mole, 25 weeks of gestation with triploidy revealed by DNA genotyping. Scattered hydropic vesicles are seen in normal placental villi
Histological features are hydropically enlarged villi with occasional central cistern and oval or irregular outline, called “fjord-like” or “scalloping” (Fig. 13.5a). Trophoblastic stromal inclusions are commonly found and the result of villous irregular shape (Fig. 13.5b). Circumferential trophoblastic hyperplasia is not conspicuous; however, focal mild syncytiotrophoblastic hyperplasia called “knuckles” or “sprouts” is a characteristic feature (Fig. 13.5c). Cytologic atypia is minimal to mild. Villous stroma sometimes contains pseudoangiomatoid change (Fig. 13.5d). Stromal fibrosis and nucleated red blood cells in villous stromal vessels, which are less common, but present, in CM, are commonly found in PM [1, 3, 15, 19].
Fig. 13.5
Histologic appearance of partial hydatidiform mole. (a) A mixed population of villi with shape differences in villous size. (b) Trophoblastic inclusions and villous stromal fibrosis. (c) “Fjord-like” irregular-shaped villi with predominantly mild syncytiotrophoblastic proliferation like “sprouts”. (d) Pseudoangiomatous change showing dilated vessels in the villous stroma
The prevalence of persistent GTD is 0.5–5% in PM, especially in the case of invasive PM [16, 17]. The risk of developing choriocarcinoma is 0–0.5% [1, 3, 20]. Differentiating PM from CM is important because CM has higher risk (15–29%) of persistent GTD. There are cases in which the morphological distinction between PM and CM, especially ECM, may be difficult because of inter-observer variation of commonly observed features, for example, edematous villi with irregular outline, mild trophoblastic hyperplasia, cistern formation, and trophoblastic pseudo-inclusions.
13.1.3 Invasive Hydatidiform Mole
Invasive hydatidiform mole is defined as CM or PM that invades the myometrium and/or uterine vessels (Fig. 13.6) [1, 21]. Clinically, these cases present with vaginal bleeding with persistent elevation of serum hCG after primary evacuation of a hydatidiform mole. Uterine perforation caused by invasive hydatidiform mole has been reported. Histologically, molar villi invading into myometrium are the diagnostic requirement. Histological features of CM or PM are same in the case of invasive hydatidiform mole. The finding of extravillous trophoblast (mainly intermediate trophoblast) without villi invading into superficial myometrium and maternal spiral artery is commonly seen in noninvasive moles and does not form the basis for a diagnosis of invasive hydatidiform mole. The incidence of invasive CM is higher than that of PM.
Fig. 13.6
Invasive complete hydatidiform mole. Molar tissue is identified in the myometrium
13.1.4 Ancillary Studies for the Diagnosis of Hydatidiform Mole
13.1.4.1 Immunohistochemistry
p57KIP2 is an effective marker for differentiating CM from partial hydatidiform mole (PM) and hydropic abortus [3, 9–11]. p57KIP2 is a cyclin-dependent kinase inhibitor encoded by the paternally imprinted and maternally expressed gene CDKN1C on chromosome 11p15.5. Due to its preferential expression from the maternal allele, the gene is silent in androgenic CM, PM, hydropic non-molar abortuses, and trisomies. These latter cases all show normal p57 protein expression pattern: positive nuclear staining in cytotrophoblast and villous stromal cells. In contrast, CM shows absent nuclear p57KIP2 staining in cytotrophoblast and villous stromal cells because CM has only paternal genome, without any maternal genome (Fig. 13.7a, b). It is important to mention that the syncytiotrophoblast is negative and intermediate trophoblast is positive for p57KIP2 in all CM, PM, and non-molar villi. This may be a pitfall for the reviewer due to inexperience in recognizing the different types of trophoblast, especially the cytotrophoblast and intermediate trophoblast, resulting in inaccurate interpretation of immunohistochemical staining pattern. It is important to carefully note which cell types show nuclear-positive staining for p57KIP2. Studies have revealed that p57 expression is highly correlated with DNA genotyping and it is a reliable marker for the diagnosis of CM. However, there are some exceptions of CM showing normal p57 pattern. For example, twin gestation with CM and normal fetus, rare CM of mosaic androgenic/biparental mosaic/chimeric gestations, and CM with retained maternal chromosome 11 are included. On the other hand, PM with p57-negative pattern based on loss of maternal chromosome rarely occurs [10]. Cell cycle proteins or proliferation markers (Ki-67, PCNA, ESF-1, CDK2, cyclin E) of molar pregnancies have also been studied and show variable results; however, none of them demonstrate the high sensitivity and specificity of p57 for use in routine diagnosis of hydatidiform mole [9].
