Placenta

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 32, and is complete hydatidiform mole of the placenta.

The information provided in this case was accurate and correct at the time of publication in 2021.

Any changes in terminology since the time of publication may not be reflected in this case.

Histologic examination shows diffusely enlarged and edematous villi with central cistern formation. There is trophoblastic hyperplasia, which is prominent and circumferential in some regions. Normal-appearing villi are not present. In combination with the gross examination and p57 immunohistochemistry, the histologic features are consistent with a complete hydatidiform mole. 

Classically, complete hydatidiform mole (CHM) presents in the second trimester with vaginal bleeding, increased uterine size, and markedly elevated serum hCG. Some patients may have a serum hCG level measuring higher than 100 x 103 mIU/mL. Less common symptoms include hyperthyroidism and hyperemesis. Ultrasound characteristically shows a “snowstorm” pattern. With advances in serum hCG measurement and early ultrasound examination, an increasing number of cases are diagnosed in the first trimester and may not demonstrate classic clinical symptoms or ultrasound findings. Risk factors for CHM include maternal age greater than 40 years and prior molar pregnancy. Recurrence is ​more likely to be seen in the setting of familial CHM but ​uncommon in sporadic CHM​.​ The risk of persistent gestational trophoblastic disease (GTD) after CHM is 15% to 20%, with fewer than 5% developing choriocarcinoma. Serial hCG levels are monitored and can be used to identify patients with persistent GTD. 

Grossly, well-developed CHM is characterized by diffuse hydropic change with variably sized semi-transparent vesicles, imparting a “grape-like” appearance. Fetal parts and normal placental components are typically not identified but may be present in rare circumstances such as twin gestations. Early in the disease course (first trimester), CHM may show minimal hydropic villous change on gross examination. 

Microscopically, CHM shows markedly enlarged and edematous villi with central cistern formation, prominent trophoblastic hyperplasia, and cytologic atypia. The trophoblastic hyperplasia is often diffuse and circumferential. Fetal tissues are absent. Very early CHM shows smaller, uniform chorionic villi with a polypoid appearance. The villi typically lack significant edema but have hypercellular villous stroma with prominent karyorrhexis. Mild to moderate trophoblastic hyperplasia may be focally present, and some cases show abortive fetal vessels. Marked cytologic atypia and mitotic activity of the implantation site are helpful features of very early CHM. 

The majority of sporadic CHM are diploid (rarely tetraploid) and entirely paternally derived with a diandric genome. Rare cases of familial CHM are biparental and associated with mutations in NLRP7 or KHDC3L. Nearly 90% of sporadic diandric cases arise from fertilization of an anuclear empty ovum by a single haploid (23X) sperm with subsequent chromosome duplication. Due to the presence of a diandric genome, p57 immunohistochemistry can be used to distinguish CHM from other entities in the histologic differential diagnosis. p57 is encoded by CDKN1C, located at 11p15.4, which is paternally imprinted and maternally expressed. The lack of a maternal genetic contribution in CHM results in absent nuclear p57 staining in cytotrophoblasts and villous stromal cells. Intermediate trophoblasts will demonstrate positive staining and serve as an internal control. Early CHM also shows absence of p57 expression and adds support to the diagnosis when minimal villous changes are present. In equivocal or difficult cases, DNA genotyping by PCR amplification of short tandem repeat loci can be used to determine parental genetic contribution and confirm a diagnosis of CHM. 

The differential diagnosis of complete hydatidiform mole includes other entities associated with hydropic change of the chorionic villi, including ​partial hydatidiform mole​​ (PHM)​, placental mesenchymal dysplasia, spontaneous hydropic abortion, and villous changes associated with chromosomal trisomy. Distinction of CHM from PHM and non-molar specimens is important since they differ in risk of persistent GTD and clinical management.  

​​​PHM typically presents with vaginal bleeding or missed/incomplete abortion in late first or early second trimester. Serum hCG may be normal or mildly elevated. Ultrasound shows focal regions of cystic change within the placenta, and a fetus may be present. The risk of persistent GTD is 1% to 5%, with choriocarcinoma occurring in <0.5% of patients. 

Several features can be used to distinguish PHM from CHM (see Table 1). Microscopically, there is a mixture of normal villi and enlarged, hydropic villi. The abnormal villi show central cistern formation, irregular villous scalloping, and stromal trophoblastic inclusions. Trophoblastic hyperplasia is mild to moderate and usually focal. Significant cytologic atypia is absent. Fetal nucleated red blood cells are common. Although some of the features of PHM may mimic those of an early CHM, the chorionic villi of early CHM are usually more uniform in size and lack scalloped contours and trophoblastic inclusions. 

PHM is nearly always triploid due to fertilization of a normal ovum by two spermatozoa, resulting in one extra paternal haploid. The majority of cases are 69XXY, while a smaller subset is 69XXX or 69XYY. PHM shows nuclear expression of p57 in cytotrophoblasts and villous stromal cells since it contains a maternal genetic complement. This finding can be used to distinguish PHM from CHM but is not helpful in differentiating PHM from other non-molar entities that show a similar p57 expression pattern. 

Table 1: CBC and differential.

Placental mesenchymal dysplasia (PMD) is a sporadic, non-molar disorder characterized by normal-appearing terminal villi admixed with large, cystically dilated stem villi demonstrating myxomatous stroma and abnormal thick-walled vessels. PMD is often accompanied by features of fetal thrombotic vasculopathy, including dilated, tortuous chorionic plate vessels with thrombosis. Trophoblastic proliferation is not present. The presence of a mixed villous population, lack of trophoblastic proliferation, and the presence of a fetus support a diagnosis of PMD over CHM. Most PMD have a diploid karyotype and have been described in association with androgenetic/biparental mosaicism. The abnormal villi of PMD have been shown to have an intermediate pattern of p57 staining, with absent nuclear expression in some or all villous stromal cells but positive staining of cytotrophoblasts.

Spontaneous hydropic abortion may show edematous villi with areas of trophoblastic proliferation, similar to early CHM. In contrast to CHM, hydropic abortuses show strong nuclear expression of p57 in cytotrophoblasts and villous stromal cells.

Abnormal villous morphology associated with trisomy may appear histologically similar to villous changes of hydatidiform moles. Chromosomal abnormalities, particularly trisomies, may be associated with enlarged, edematous villi and cistern formation. Some gestations may also show villi with scalloped borders. In contrast to CHM, there is often a mixture of normal and hydropic villi and focal trophoblastic proliferation. Strong nuclear expression of p57 is present in cytotrophoblasts and villous stromal cells.

1. Which of the following statements is true regarding sporadic complete hydatidiform moles (CHM)?
   
   
   1. CHM are entirely paternally derived.
   2. Most cases are diagnosed in the third trimester.
   3. Serum hCG is often only mildly elevated.
   4. There is a mixed population of normal and hydropic villi.
   5. Villi often demonstrate abnormal, thick-walled vessels.
2. Which of the following is more likely to be present in CHM than partial hydatidiform mole?
   
   
   1. Mixed population of normal and hydropic villi
   2. Positive p57 expression in villous stromal cells and cytotrophoblasts
   3. Presence of a fetus
   4. Pronounced circumferential trophoblastic hyperplasia
   5. Triploid karyotype
3. Which of the following is most likely to show regions of cystically dilated stem villi with myxomatous stroma and thick-walled blood vessels?
   
   
   1. Abnormal villous morphology associated with trisomy
   2. Complete hydatidiform mole
   3. Partial hydatidiform mole
   4. Placental mesenchymal dysplasia
   5. Spontaneous hydropic abortion

1. Banet N, DeScipio C, Murphy KM, et al. Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping. Mod Pathol. 2014;27(2):238-254.
2. Berkowitz RS, Goldstein DP. Clinical practice: molar pregnancy. N Engl J Med. 2009;360(16):1639-1645.
3. Ernst LM. Placental mesenchymal dysplasia. J Fetal Med. 2015;2:127-133.
4. Hui P, Buza N, Sebire NJ, et al. Gestational trophoblastic disease. In: WHO Classification of Tumours Editorial Board. Female Genital Tumours. 5th ed. IARC Press.
5. Norris-Kirby A, Hagenkord JM, Kshirsagar MP, Ronnett BM, Murphy KM. Abnormal villous morphology associated with triple trisomy of paternal origin. J Molec Diagn. 2010;12(4):525-529.
6. Romaguera RL, Rodriguez MM, Bruce JH, et al. Molar gestations and hydropic abortions differentiated by p57 immunostaining. Fetal Pediatr Pathol. 2004;23(2-3);181-190.
7. Ronnett BM. Hydatidiform moles: ancillary techniques to refine diagnosis. Arch Pathol Lab Med. 2018;142:1485-1502.

1. CHM are entirely paternally derived (a)
2. Pronounced circumferential trophoblastic hyperplasia (d)
3. Placental mesenchymal dysplasia (d)