Gestational Trophoblastic Disease

8.1 NONMOLAR HYDROPIC ABORTUS VS. PARTIAL HYDATIDIFORM MOLE

	Nonmolar Hydropic Abortus	Partial Hydatidiform Mole
Age	Reproductive years (15-46 years)	Reproductive years (13-45 years)
Location	Uterus; occasionally ectopic in fallopian tubes	Uterus; rarely ovaries and fallopian tubes
Symptoms	Usual presentation as missed or incomplete abortion	Usual presentation as missed or incomplete abortion in late first or early second trimester
Signs	Usual presentation as missed or incomplete abortion	Usual presentation as missed or incomplete abortion; may have focal cystic changes on ultrasound; serum β-hCG may be elevated
Etiology	Early pregnancy loss	Diandric triploid conception with nearly all being dispermic
Histology	1. Enlarged, hydropic chorionic villi; usually not as large as in partial moles	1. Enlarged, hydropic chorionic villi; may be larger than in nonmolar cases (Fig. 8.1.6)
	2. Villi tend to be more symmetrically rounded than in partial moles but can be occasionally slightly irregular (Figs. 8.1.1 8.1.2, 8.1.3)	2. Variably irregular villous contours (“scalloping”) (Fig. 8.1.7)
	3. Usually no villous trophoblastic hyperplasia, but occasional focal mild hyperplasia can be seen (Fig. 8.1.4); villi have polarization of trophoblast (Fig. 8.1.5)	3. Variable villous trophoblastic hyperplasia (Fig. 8.1.8); often greater than in nonmolar cases, but may be limited and mild (Figs. 8.1.9 and 8.1.10); villi lack polarization of trophoblast
	4. Trophoblastic inclusions in villi typically absent	4. Focal trophoblastic inclusions in villi may be present (Fig. 8.1.11)
	5. Nucleated red blood cells may be present in villi	5. Nucleated red blood cells may be present in villi
	6. Fetal parts may be present	6. Fetal parts may be present
Special studies	• p57 immunohistochemistry (+) in villous cytotrophoblast and stroma	• p57 immunohistochemistry (+) in villous cytotrophoblast and stroma
	• Genotyping: biparental diploid (or tetraploid); uncommonly, genotyping may reveal mosaic/chimeric or digynic triploid conception	• Genotyping: almost always diandric triploid, rarely triandric tetraploid
	• Usual karyotype, XX or XY; trisomies can occur	• XXY most common karyotype followed by XXX and XYY
Treatment	Dilation and evacuation/curettage	Dilation and evacuation/curettage; follow-up with serum β-hCG measurement; contraception during follow-up period
Prognosis	Unremarkable	Risk of persistent gestational trophoblastic disease and subsequent choriocarcinoma, 0.5%-5% and <0.5%, respectively

Figure 8.1.1 Nonmolar hydropic abortus with mostly round chorionic villi. Only minimal and limited trophoblastic hyperplasia is noted.

Figure 8.1.2 Nonmolar hydropic abortus with slightly irregular villi. This case was digynic triploid by genotyping, which is incompatible with a diagnosis of a partial mole (the latter is diandric triploid by definition). Digynic triploid conceptions can have some abnormal villous morphology that can histologically overlap with a partial mole.

Figure 8.1.3 Nonmolar hydropic abortus. Some villi are mostly round, while others are slightly irregular. This morphology can create concern for a partial mole. However, no appreciable trophoblastic hyperplasia is present.

Figure 8.1.4 Nonmolar hydropic abortus with some degree of trophoblastic hyperplasia. This case was biparental diploid by genotyping but also had trisomy of chromosome 13. Trisomies can be associated with abnormal villous morphology, which histologically mimics a partial mole.

Figure 8.1.5 Nonmolar hydropic abortus showing polarization of trophoblast.

Figure 8.1.6 Partial hydatidiform mole with enlarged molar villus containing a cistern.

Figure 8.1.7 Partial hydatidiform mole with villous scalloping.

Figure 8.1.8 Partial hydatidiform mole with trophoblastic hyperplasia.

Figure 8.1.9 Partial hydatidiform mole. Some villi are round as in nonmolar hydropic abortuses. However, some villi demonstrate mild scalloping. Mild trophoblastic hyperplasia is noted in the lower right.

Figure 8.1.10 Partial hydatidiform mole, status postmethotrexate therapy, with fibrotic villi and no appreciable trophoblastic hyperplasia. This case was diandric triploid by genotyping and shows features that can be seen in partial moles treated with methotrexate.

Figure 8.1.11 Partial hydatidiform mole with trophoblastic inclusions.

8.2 PARTIAL MOLE VS. COMPLETE MOLE (INCLUDING THE EARLY VARIANT)

	Partial Mole	Complete Mole (Including the Early Variant)
Age	Reproductive years (13-45 years)	14-55 years
Location	Uterus; rarely ovaries and fallopian tubes	Uterus; rarely ovaries and fallopian tubes
Symptoms	Usual presentation as missed or incomplete abortion in late first or early second trimester	Usual presentation as missed or incomplete abortion in late first or early second trimester; can have hyperemesis
Signs	Usual presentation as missed or incomplete abortion; may have focal cystic changes on ultrasound; serum β-hCG may be elevated	Usual presentation as missed or incomplete abortion; uterus can be enlarged; may have pre-eclampsia or hyperthyroidism; may have snow storm pattern without presence of fetus on ultrasound; serum β-hCG can be markedly elevated
Etiology	Diandric triploid conception with nearly all being dispermic	Androgenetic diploid conception with most being monospermic
Histology	1. Enlarged, hydropic chorionic villi	1. Enlarged, hydropic chorionic villi; may be larger than in partial moles
	2. Variably irregular villous contours (“scalloping”) (Fig. 8.2.1)	2. Typically do not have irregular villous contours (“scalloping”) as seen in partial moles; early complete moles may have bulbous “cauliflower-like” shapes
	3. Villous cisterns may be present	3. Villous cisterns may be present
	4. Villous stroma usually not myxoid and typically lacks “canalicular” vascular pattern	4. Villous stroma may be myxoid with “canalicular” vascular pattern
	5. Villous stroma may contain mild amount of apoptotic debris, but not as abundant as in some complete moles	5. Villous stroma may contain abundant apoptotic debris
	6. Variable villous trophoblastic hyperplasia (Figs. 8.2.2 and 8.2.3); not as marked or circumferential as in complete moles	6. Marked villous trophoblastic hyperplasia (typically circumferential) (Figs. 8.2.6 8.2.7, 8.2.8, 8.2.9); often greater than in partial moles; hyperplasia in early complete moles may be limited
	7. Atypical exaggerated implantation site usually absent	7. Atypical exaggerated implantation site may be seen
	8. Focal trophoblastic inclusions in villi may be present	8. Focal trophoblastic inclusions in villi may be present
	9. Nucleated red blood cells may be present in villi (Fig. 8.2.4)	9. Nucleated red blood cells absent in villi
	10. Fetal parts may be present	10. Fetal parts absent except in rare cases of complete moles arising in multiple gestation pregnancies (Fig. 8.2.10)
Special studies	• p57 immunohistochemistry (+) in villous cytotrophoblast and stroma (Fig. 8.2.5)	• p57 immunohistochemistry (-) in villous cytotrophoblast and stroma (Figs. 8.2.9 8.2.10, 8.2.11)
	• Genotyping: almost always diandric triploid, rarely triandric tetraploid	• Genotyping: almost always androgenetic diploid, rarely androgenetic tetraploid; rare recurrent, familial, and biparental complete moles due to NALP7/NLRP7 mutations have been described
	• XXY most common karyotype followed by XXX and XYY	• Karyotype in majority of cases, XX; minority are XY
Treatment	Dilation and evacuation/curettage; follow-up with serum β-hCG measurement; contraception during follow-up period	Dilation and evacuation/curettage; follow-up with serum β-hCG measurement; contraception during follow-up period; chemotherapy for cases in which serum β-hCG does not return to normal
Prognosis	Risk of persistent gestational trophoblastic disease and subsequent choriocarcinoma, 0.5%-5% and <0.5%, respectively	Risk of persistent gestational trophoblastic disease and subsequent choriocarcinoma, 15%-29% and 2%-3%, respectively

Figure 8.2.1 Partial hydatidiform mole with scalloping.

Figure 8.2.2 Partial hydatidiform mole with notable trophoblastic hyperplasia.

Figure 8.2.3 Partial hydatidiform mole with mild trophoblastic hyperplasia.

Figure 8.2.4 Partial hydatidiform mole with nucleated red blood cells within molar villi.

Figure 8.2.5 Partial hydatidiform mole. p57 immunostain shows positivity in the cytotrophoblast layer and stroma of a molar villus.

Figure 8.2.6 Complete hydatidiform mole with circumferential villous trophoblastic hyperplasia.

Figure 8.2.7 Complete hydatidiform mole with circumferential villous trophoblastic hyperplasia.

Figure 8.2.8 Complete hydatidiform mole with marked villous trophoblastic hyperplasia.

Figure 8.2.9 Complete hydatidiform mole. p57 immunostain shows loss of expression in the cytotrophoblast layer and stroma of a molar villus. Note that intervillous intermediate trophoblast (seen on either side of the villus) are positive in complete moles serving as a positive internal control.

Figure 8.2.10 Complete hydatidiform mole arising in the setting of a twin pregnancy. The combination of 2 types of villi (complete mole [left] and normal [right]) can be mistaken for a partial mole.

Figure 8.2.11 Same case as Figure 8.2.10. p57 immunostain showing loss of expression in the cytotrophoblast layer and stroma of a molar villus (left) and positivity in the nonmolar villus (center and right). Failure to recognize two morphologically different populations can result in incorrect interpretation of the immunostain and misclassification as a partial mole because of some positivity in the specimen.

8.3 EARLY COMPLETE HYDATIDIFORM MOLE VS. NONMOLAR HYDROPIC ABORTUS

	Early Complete Hydatidiform Mole	Nonmolar Hydropic Abortus
Age	14-55 years	Reproductive years (15-46 years)
Location	Uterus; rarely ovaries and fallopian tubes	Uterus; occasionally ectopic in fallopian tubes
Symptoms	Usual presentation as missed or incomplete abortion in first trimester	Usual presentation as missed or incomplete abortion
Signs	Usual presentation as missed or incomplete abortion; serum β-hCG can be normal or elevated	Usual presentation as missed or incomplete abortion
Etiology	Androgenetic diploid conception with most being monospermic	Early pregnancy loss
Histology	1. Enlarged, hydropic chorionic villi	1. Enlarged, hydropic chorionic villi
	2. Villi may have bulbous “cauliflower-like” shapes (Fig. 8.3.1)	2. Villi tend to be symmetrically rounded but can be occasionally slightly irregular (Fig. 8.3.8)
	3. Villous cisterns may be present (Fig. 8.3.2)	3. No villous cisterns
	4. Villous stroma often myxoid with “canalicular” vascular pattern (Fig. 8.3.3)	4. Villous stroma often lacks both myxoid appearance and “canalicular” vascular pattern
	5. Villous stroma often contains abundant apoptotic debris (Fig. 8.3.3)	5. Villous stroma often lacks abundant apoptotic debris
	6. Villous trophoblastic hyperplasia can be marked and may be circumferential; however, hyperplasia in early complete moles can be limited (Figs. 8.3.4 and 8.3.5); villi lack polarization of trophoblast	6. Usually no villous trophoblastic hyperplasia (Fig. 8.3.8), but occasional focal mild hyperplasia can be seen (Fig. 8.3.9); villi have polarization of trophoblast (Fig. 8.3.10)
	7. Atypical exaggerated implantation site may be seen (Fig. 8.3.6) (exaggerated implantation sites associated with complete moles have greater cytologic atypia than in nonmolar cases)	7. Atypical exaggerated implantation site absent
	8. Focal trophoblastic inclusions in villi may be present	8. Trophoblastic inclusions in villi typically absent
	9. Nucleated red blood cells absent in villi	9. Nucleated red blood cells may be present in villi
	10. Fetal parts absent except in rare cases of complete moles arising in multiple gestation pregnancies	10. Fetal parts may be present
Special studies	• p57 immunohistochemistry (-) in villous cytotrophoblast and stroma (Fig. 8.3.7)	• p57 immunohistochemistry (+) in villous cytotrophoblast and stroma (Fig. 8.3.11)
	• Genotyping: almost always androgenetic diploid, rarely androgenetic tetraploid; rare recurrent, familial, and biparental complete moles due to NALP7/NLRP7 mutations have been described	• Genotyping: biparental diploid (or tetraploid); uncommonly, genotyping may reveal mosaic/chimeric or digynic triploid conception
	• Karyotype in majority of cases, XX; minority are XY	• Usual karyotype, XX or XY; trisomies can occur
Treatment	Dilation and evacuation/curettage; follow-up with serum β-hCG measurement; contraception during follow-up period; chemotherapy for cases in which serum β-hCG does not return to normal	Dilation and evacuation/curettage
Prognosis	Risk of persistent gestational trophoblastic disease and subsequent choriocarcinoma, 15%-29% and 2%-3%, respectively	Unremarkable

Figure 8.3.1 Early complete hydatidiform mole with bulbous “cauliflower-like” villous shapes.

Figure 8.3.2 Early complete hydatidiform mole with cistern formation.

Figure 8.3.3 Early complete hydatidiform mole with myxoid stroma, canalicular vessels, and apoptotic debris within a villus.

Figure 8.3.4 Early complete hydatidiform mole showing mild trophoblastic hyperplasia. Note that the hyperplasia is nonpolarized.

Figure 8.3.5 Early complete hydatidiform mole. In this field, the villi are round without evident trophoblastic hyperplasia, mimicking a nonmolar hydropic abortus.

Figure 8.3.6 Early complete hydatidiform mole with atypical implantation site.

Figure 8.3.7 Early complete hydatidiform mole. p57 immunostain shows loss of expression in the villous cytotrophoblast layer and villous stromal cells. Adjacent to the villus is an intervillous trophoblastic island with p57 expression serving as a positive internal control.

Figure 8.3.8 Nonmolar hydropic abortus. The hydropic villi are round without trophoblastic hyperplasia.

Figure 8.3.9 Nonmolar hydropic abortus. This early/immature conception exhibits much greater trophoblastic hyperplasia than is usually seen in a nonmolar hydropic abortus, the latter typically being mild and focal when present. However, early/immature conceptions can simulate an early complete mole.

Figure 8.3.10 Nonmolar hydropic abortus with polarized trophoblast.

Figure 8.3.11 Nonmolar hydropic abortus. p57 immunostain shows positivity in the villous cytotrophoblast layer and villous stromal cells.

8.4 COMPLETE HYDATIDIFORM MOLE WITH ATYPICAL TROPHOBLASTIC HYPERPLASIA VS. CHORIOCARCINOMA

	Complete Hydatidiform Mole with Atypical Trophoblastic Hyperplasia	Choriocarcinoma
Age	14-55 years	Reproductive years
Location	Uterus; rarely ovaries and fallopian tubes	Often in uterus; occasionally in the fallopian tube or ovary
Symptoms	Usual presentation as missed or incomplete abortion in late first or early second trimester; can have hyperemesis	Vaginal bleeding
Signs	Usual presentation as missed or incomplete abortion; uterus can be enlarged; may have preeclampsia or hyperthyroidism; may have snow storm pattern without presence of fetus on ultrasound; serum β-hCG can be markedly elevated	Serum β-hCG is markedly elevated; may have persistent gestational trophoblastic disease
Etiology	Androgenetic diploid conception with most being monospermic	A subset of cases have an antecedent complete mole, but many choriocarcinomas develop after a normal pregnancy
Histology	1. Molar villi are present with marked circumferential trophoblastic hyperplasia, which may be extensive (Fig. 8.4.1)	1. Molar villi may or may not be present; some investigators do not accept a diagnosis of choriocarcinoma in the presence of molar villi (however, choriocarcinoma in the presence of normal villi, such as an intraplacental choriocarcinoma, is allowed [Figs. 8.4.5 and 8.4.6]), while others do accept a diagnosis of choriocarcinoma in a background of a complete mole
	2. Detached fragments of atypical trophoblast may qualitatively resemble choriocarcinoma (Figs. 8.4.2 8.4.3, 8.4.4)	2. The atypical trophoblast proliferation contains sheets of trimorphic malignant cells, which include cytotrophoblast, intermediate trophoblast, and syncytiotrophoblast; the architecture of these intimately admixed populations resembles the arrangement seen in their normal counterparts, in which cytotrophoblast are rimmed by syncytiotrophoblast (Figs. 8.4.7 and 8.4.8); tissue invasion (Fig. 8.4.9), hemorrhage, and necrosis are present; lymphovascular space invasion is frequent
	3. Atypical trophoblast lack tissue invasion	3. Criteria for diagnosing choriocarcinoma in the setting of a complete mole: cytologically malignant trophoblastic proliferation, separate from molar villi and morphologically indistinguishable from choriocarcinoma, must display evidence of tissue invasion
Special studies	• p57 immunohistochemistry (-) in villous cytotrophoblast and stroma	• p57 immunohistochemistry (-) in villous cytotrophoblast and stroma (if villi are present), as the type of mole that a choriocarcinoma typically arises within is the complete type
	• Genotyping: almost always androgenetic diploid, rarely androgenetic tetraploid; rare recurrent, familial, and biparental complete moles due to NALP7/NLRP7 mutations have been described	• Complex karyotypes can occur
	• Karyotype in majority of cases, XX; minority are XY	• Majority of cases will have XX sex chromosome component; most cases lack a Y chromosome
Treatment	Dilation and evacuation/curettage; follow-up with serum β-hCG measurement; contraception during follow-up period; chemotherapy for cases in which serum β-hCG does not return to normal	Chemotherapy
Prognosis	Risk of persistent gestational trophoblastic disease and subsequent choriocarcinoma, 15%-29% and 2%-3%, respectively	Favorable outcome with chemotherapy

Figure 8.4.1 Complete hydatidiform mole with atypical trophoblastic hyperplasia (left). Molar villi are present in the center of this field, while gestational endometrium is located on the right.

Figure 8.4.2 Complete hydatidiform mole showing detached fragments of atypical trophoblast.

Figure 8.4.3 Same case as Figure 8.4.2. Intimate arrangement of two populations of trophoblast qualitatively identical to choriocarcinoma.

Figure 8.4.4 Complete hydatidiform mole with sheets of atypical trophoblast, which can simulate choriocarcinoma.

Figure 8.4.5 Intraplacental choriocarcinoma (choriocarcinoma, upper left; term placenta, lower right).

Figure 8.4.6 Same case as Figure 8.4.5 (choriocarcinoma, upper left; term placenta, lower right).

Figure 8.4.7 Choriocarcinoma with intimate arrangement of two populations of trophoblast.

Figure 8.4.8 Choriocarcinoma showing intimate arrangement of two populations of trophoblast. Note the syncytiotrophoblastic component with abundant amphophilic cytoplasm rims the mononuclear component.

Figure 8.4.9 Choriocarcinoma with tissue invasion.

8.5 MOSAIC/CHIMERIC CONCEPTION VS. PARTIAL HYDATIDIFORM MOLE

	Mosaic/Chimeric Conception	Partial Hydatidiform Mole
Age	Reproductive years (18-45 years)	Reproductive years (13-45 years)
Location	Uterus	Uterus; rarely ovaries and fallopian tubes
Symptoms	Usual presentation as missed or incomplete abortion in late first or early second trimester	Usual presentation as missed or incomplete abortion in late first or early second trimester
Signs	Usual presentation as missed or incomplete abortion; may have ultrasound findings suggesting a molar pregnancy; serum β-hCG may be elevated if coexisting complete hydatidiform mole is present	Usual presentation as missed or incomplete abortion; may have focal cystic changes on ultrasound; serum β-hCG may be elevated
Etiology	Conception resulting in mixture of two cell lines (one androgenetic, the other biparental) arising by either mosaicism (mitotic error in a single zygote) or chimerism (fusion of two different zygotes)	Diandric triploid conception with nearly all being dispermic
Histology	1. Enlarged, hydropic chorionic villi (Fig. 8.5.1)	1. Enlarged, hydropic chorionic villi
	2. Variably sized and irregularly shaped villi	2. Variably irregular villous contours (“scalloping”) (Fig. 8.5.7)
	3. Some villi will have hypercellular stroma (Fig. 8.5.2)	3. No villi with hypercellular stroma
	4. Villous cisterns may be present	4. Villous cisterns may be present
	5. Focal trophoblastic inclusions in villi may be present	5. Focal trophoblastic inclusions in villi may be present
	6. Nonmolar mosaic/chimeric villi lack trophoblastic hyperplasia; villi have polarization of trophoblast	6. Variable villous trophoblastic hyperplasia (Fig. 8.5.8); may be limited and mild; villi lack polarization of trophoblast
	7. Coexisting component of complete hydatidiform mole will be present in some cases (Figs. 8.5.3 and 8.5.4)	7. No component of complete mole
	8. Nucleated red blood cells may be present in nonmolar villi	8. Nucleated red blood cells may be present in villi
	9. Fetal parts may be present	9. Fetal parts may be present
Special studies	• p57 immunohistochemistry (in individual nonmolar villi): discordant pattern ([+] in villous cytotrophoblast (biparental population), [-] in villous stroma [androgenetic population]) (Fig. 8.5.5) • p57 immunohistochemistry (component of complete mole, if present): (-) in villous cytotrophoblast and stroma (Fig. 8.5.6) • Genotyping (nonmolar villi; >1 villous area should be analyzed): excess of paternal alleles with variable paternal:maternal allele ratios, >2:1 • Genotyping (component of complete mole, if present): androgenetic diploid • FISH analysis (nonmolar villous component): both cytotrophoblast and stroma are usually diploid (often XX in both cell types), but discordant ploidy between cytotrophoblast vs. stroma can occur	• p57 immunohistochemistry (+) in villous cytotrophoblast and stroma (Fig. 8.5.9) • Genotyping: almost always diandric triploid, rarely triandric tetraploid • XXY most common karyotype followed by XXX and XYY
Treatment	Dilation and evacuation/curettage; for cases without a molar component, follow-up with serum β-hCG measurement is recommended because of the presence of an androgenetic cell line; contraception during follow-up period; cases with a component of a complete mole should be managed accordingly	Dilation and evacuation/curettage; follow-up with serum β-hCG measurement; contraception during follow-up period
Prognosis	For cases without a molar component, outcome data are limited; cases with a component of complete mole would be expected to have prognosis similar to conventional complete moles	Risk of persistent gestational trophoblastic disease and subsequent choriocarcinoma, 0.5%-5% and <0.5%, respectively

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Tags: Differential Diagnoses in Surgical Pathology: Gynecologic Tract

Sep 25, 2018 | Posted by drzezo in PATHOLOGY & LABORATORY MEDICINE | Comments Off

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