College of American Pathologists

2012 — December Case of the Month

Posted December 6, 2012


CAP Foundation Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 35-year-old woman presented at 10 weeks (by LMP) with vaginal bleeding. A ß-HCG level was obtained and measured 345,000; by report, a subsequent ultrasound was considered “abnormal.” A D & C was performed. Multiple fragments of blood clot admixed with enlarged hydropic-appearing villi measuring 8.0 x 5.0 x 1.0 cm were submitted. No fetal parts were grossly identified.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 37, and is complete hydatidiform mole.

Criteria for Diagnosis and Comments:
The histologic findings are diagnostic of a complete hydatidiform mole (CHM). They include (1) enlarged hydropic, and frequently cavitated villi, in which the cavitations are due to central necrosis resulting in cystic spaces or cisterns, (2) concentric cytotrophoblastic and syncytiotrophoblastic proliferation around the villous structures, sometimes forming a “medusa”-like appearance and (3) atypical implantation site, in which there is significant cytologic atypia of the intermediate trophoblastic cells within the decidual implantation site.

The spectrum of gestational trophoblastic disease (GTD) includes hydatidiform molar pregnancies (CHM, partial hydatidiform mole, and invasive mole), as well as non-molar lesions (placental site nodule, epithelioid trophoblastic tumor, placental site trophoblastic tumor and choriocarcinoma). Hydatidiform moles represent abnormally developed placental tissue, of which the hallmark is the presence of marked enlargement of the chorionic villi.

Patients with CHM are typically >40 years of age and most commonly present with abnormal vaginal bleeding. Typically, the uterus is enlarged greater than expected for dates and fetal heart sounds are not identified. Urine and serum ß-HCG levels are usually markedly elevated (>100,000 miU/ml) and symptoms related to these elevated levels, such as toxemia of early pregnancy or severe hyperemesis, may also occur. Ultrasound examination may show the classic "snowstorm" appearance with the uterine cavity filled with numerous, hypoechoic areas ranging from 3 to 10 mm; a fetus is not identified. The classic histologic features are as described above; however, recognition of CHM earlier in its natural history can be achieved when the following histologic features are present: (1) scattered slightly enlarged cavitated villi with concentric trophoblastic hyperplasia and atypia, (2) hypercellular villous stroma within a blue myxoid matrix, (3) prominent karyorrhexis of villous mesenchymal cells, (4) irregular villous contours with bulbous protrusions imparting a “cauliflower”-like appearance and (5) implantation site atypia. Genetically, CHM are typically androgenetic diploid with a 46,XX karyotype as a result of fertilization of an empty egg by a sperm with subsequent genome duplication (i.e. the genetic material is derived exclusively from the paternal genome). Since CHM are paternally derived, paternally imprinted genes that are normally expressed exclusively from maternally derived chromosomes should be absent. Studies have shown that p57KIP2, a paternally imprinted, maternally expressed gene, is useful in confirming the diagnosis of a complete mole, as the villous mesenchymal cells and villous cytotrophoblast of CHM are negative for this marker. Treatment consists of complete evacuation of the molar gestation and monitoring of serum ß-HCG levels for 6 – 12 months (or until they normalize) to evaluate for the possibility of persistent trophoblastic disease, which occurs in approximately 20% of women with a prior CHM. Persistent trophoblastic disease may represent persistent mole with no myometrial invasion, an invasive mole, or a choriocarcinoma (occurring in approximately 2 – 3% of women with prior CHM). Persistent trophoblastic disease is treated with chemotherapy with a cure rate approaching 100%.

Partial hydatidiform mole (PHM) differs from CHM by the following clinical and pathologic features: (1) patients with PHM have a normal or only slightly enlarged uterus for expected gestational age, (2) fetal heart tones are frequently identified, (3) ß-HCG levels are normal or only slightly elevated, (4) fetal abnormalities may be present, particularly syndactyly involving the third and fourth finger, (5) enlarged hydropic villi are admixed with normal appearing villi (6) the enlarged villi often have scalloped contours with trophoblastic inclusions (7) there is usually only mild concentric syncytiotrophoblastic hyperplasia that often has a lacy appearance, (8) evidence of fetal development (in the form on nucleated red blood cells within villous capillaries, amnion, chorion or fetal tissue) is typically present, (9) they are genetically diandric triploid gestations (fertilization of an egg by two sperm), (10) they are p57KIP2 positive and (11) are rarely associated with persistent trophoblastic disease.

Hydropic abortus differs from CHM as (1) it typically is not associated with a markedly elevated ß-HCG level, (2) the volume of tissue removed is typically much less than that with CHM, (3) the villi appear swollen but lack true cistern formation, (4) the villi typically have a degenerative appearance in keeping with early embryonic demise, (5) the trophoblastic proliferation has a polar distribution with the formation of trophoblastic columns at one end of the villous and (6) are p57KIP2 positive.

Choriocarcinoma usually follows a (molar or non-molar) pregnancy by an interval of several months; approximately 50% of these tumors occur subsequent to a complete molar gestation. The finding of molar villi excludes the diagnosis of a choriocarcinoma. In rare instances of choriocarcinoma occurring concurrently with a normal gestation, it is typically seen in a non-molar third trimester placenta.

Supplementary Questions: For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which entity is associated with uterine enlargement greater than expected for dates, a markedly elevated ß-HCG level (>100,000 miU/ml) and histologic features which include diffusely enlarged, often cavitated villi with concentric trophoblastic proliferation? A. Complete Hydatidiform Mole
B. Hydropic Abortus
C. Partial Hydatidiform Mole
2. Which entity is associated with the greatest risk for persistent gestational trophoblastic disease? A. Complete Hydatidiform Mole
B. Hydropic Abortus
C. Partial Hydatidiform Mole
3. Which entity is associated with a lack of immunostaining for the paternally imprinted, maternally expressed gene product, p57KIP2 in villous mesenchymal cells and villous cytotrophoblast? A. Complete Hydatidiform Mole
B. Hydropic Abortus
C. Partial Hydatidiform Mole


  1. Castrillon DH, Sun D, Weremowicz S, et al. Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2. Am J Surg Pathol. 2001;25:(10):1225-1230.
  2. Elvin JA, Crum CP, Genest DR. Complications of early pregnancy, including trophoblastic neoplasia. In: Crum CP, Lee KR, eds. Diagnostic Obstetrical and Gynecologic Pathology. 1st ed. Philadelphia, PA: Elsevier Saunders; 2006.
  3. Shih I-M. Gestational trophoblastic lesions. In: Nucci MR, Oliva E, eds. Gynecologic Pathology: A Volume in the Series Foundations in Diagnostic Pathology. 1st ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2009.

Marisa R. Nucci, MD FCAP
Surgical Pathology Committee
Brigham and Women’s Hospital
Boston, MA