Placental Mesenchymal Dysplasia Is Associated With High Rates of Intrauterine Growth Restriction and Fetal Demise: A Report of 11 New Cases and a Review of the Literature

Truc Pham, MD; Julie Steele, MD; Carla Stayboldt, MD; Linda Chan, MD; Kurt Benirschke, MD

Disclosures

Am J Clin Pathol. 2006;126(1):67-78. 

In This Article

Results

Clinical Findings

We examined 11 new cases of PMD ( Table 1 ). (No clinical or gross placental data were available for case 11.) Maternal ages ranged from 22 to 33 years. Except for case 1 with preeclampsia, the available maternal history in all cases was noncontributory; however, detailed medical histories were lacking with regard to the presence of thrombophilic states, such as antiphospholipid syndrome, genetic polymorphism for factor V, prothrombin, and methyltetrahydrofolate reductase (MTHFR), and autoimmune disorders. The gestational periods ranged from 30 to 37 weeks. In case 6, a transabdominal ultrasound study at 23 weeks' gestation showed a placenta with multiple 3- to 9-mm, hypoechoic cysts, suggestive of a partial hydatidiform mole (Figure 1). The concurrent maternal serum β human chorionic gonadotropin level was normal (10,300 mIU/mL [10,300 IU/L]). Similarly, in case 9, serial ultrasound studies showed a cystic placenta suggestive of a partial mole. Five fetuses were females. Sex data were unavailable for the other 6 cases. Based on available data, 6 fetuses had IUGR, and 4 of these were stillborn. No fetuses or newborns had BWS. One fetus (case 2) had a congenital hepatic mesenchymal hamartoma as noted in a pathology report. The histologic slides of this lesion were not available for review.

Figure 1.

Transabdominal ultrasound study at 23 weeks' gestation showing a placenta with multiple 3- to 9-mm, hypoechoic cysts, suggestive of a partial hydatidiform mole.

Gross and Histologic Findings

The average unfixed placental weight was 863 g (2.31 multiples of median [MoM]; normal medians referenced from established report).[9] The weight of the placenta in case 3 was obtained after formalin fixation; as such, the actual unfixed weight likely was lighter than the apparent weight (approximately 8% lighter).[10]

Four cases had abnormal umbilical cords, including a tortuous and markedly right-twisted cord, an excessively long cord with marked left twist, a single-artery umbilical cord, and a cord with furcate (branched) insertion. Varicose dilation of fetal chorionic vessels was present in all cases (Figure 2).

Figure 2.

Fetal surfaces of representative placentas with mesenchymal dysplasia showing typical cirsoid dilation and thrombosis of chorionic vessels. A, Case 5, moderately enlarged chorionic vessels (arrows) and excessively long umbilical cord with marked right twists. B, Case 6, markedly dilated periumbilical chorionic vessels, maximum diameter 3 cm. C, Case 4, prominent varicose chorionic vessels.

Figure 2.

Fetal surfaces of representative placentas with mesenchymal dysplasia showing typical cirsoid dilation and thrombosis of chorionic vessels. A, Case 5, moderately enlarged chorionic vessels (arrows) and excessively long umbilical cord with marked right twists. B, Case 6, markedly dilated periumbilical chorionic vessels, maximum diameter 3 cm. C, Case 4, prominent varicose chorionic vessels.

Figure 2.

Fetal surfaces of representative placentas with mesenchymal dysplasia showing typical cirsoid dilation and thrombosis of chorionic vessels. A, Case 5, moderately enlarged chorionic vessels (arrows) and excessively long umbilical cord with marked right twists. B, Case 6, markedly dilated periumbilical chorionic vessels, maximum diameter 3 cm. C, Case 4, prominent varicose chorionic vessels.

Cut surfaces showed heterogeneous areas of abnormal tan and gelatinous and normal red-brown and spongy villous tissues (Figure 3). The dysplastic tissue constituted up to 80% of the placental volume. Focal infarcts and intervillous thrombi were noted.

Figure 3.

Cut surfaces of placental mesenchymal dysplasia. A, Case 4. Thick placenta with discrete subchorionic nodule and marginal segment of gelatinous parenchyma, adjacent to apparent normal spongy parenchyma. B, Case 4. Higher magnification of a dilated, thrombosed chorionic vessel in another section. C, Case 4. Closer view of enlarged, edematous villi compared with adjacent normal villi. D, Case 6. Early ischemic infarct accentuated by immersion in Perl solution. Infarcted tissue stained deep blue due to iron accumulation.

Figure 3.

Cut surfaces of placental mesenchymal dysplasia. A, Case 4. Thick placenta with discrete subchorionic nodule and marginal segment of gelatinous parenchyma, adjacent to apparent normal spongy parenchyma. B, Case 4. Higher magnification of a dilated, thrombosed chorionic vessel in another section. C, Case 4. Closer view of enlarged, edematous villi compared with adjacent normal villi. D, Case 6. Early ischemic infarct accentuated by immersion in Perl solution. Infarcted tissue stained deep blue due to iron accumulation.

Figure 3.

Cut surfaces of placental mesenchymal dysplasia. A, Case 4. Thick placenta with discrete subchorionic nodule and marginal segment of gelatinous parenchyma, adjacent to apparent normal spongy parenchyma. B, Case 4. Higher magnification of a dilated, thrombosed chorionic vessel in another section. C, Case 4. Closer view of enlarged, edematous villi compared with adjacent normal villi. D, Case 6. Early ischemic infarct accentuated by immersion in Perl solution. Infarcted tissue stained deep blue due to iron accumulation.

Figure 3.

Cut surfaces of placental mesenchymal dysplasia. A, Case 4. Thick placenta with discrete subchorionic nodule and marginal segment of gelatinous parenchyma, adjacent to apparent normal spongy parenchyma. B, Case 4. Higher magnification of a dilated, thrombosed chorionic vessel in another section. C, Case 4. Closer view of enlarged, edematous villi compared with adjacent normal villi. D, Case 6. Early ischemic infarct accentuated by immersion in Perl solution. Infarcted tissue stained deep blue due to iron accumulation.

Surface vessels were markedly dilated, up to 3.0 cm in diameter, and thrombosed. The vascular walls were markedly stretched and extensively degenerated. In some cases, transmural medial necrosis was noted (Figure 4). Intimal cushions with fibrous organization were found in all cases. Many vessels had endothelial damage, hemorrhage into the vessel wall, and fibroblastic organization. These changes have been described by Sander[11] as "hemorrhagic endovasculitis" and by Redline et al[12] as "villous stromal-vascular karyorrhexis." These changes were found most often in cases with IUFD. Villous chorangiosis (hypercapillarization), defined as more than 10 terminal villi showing 10 or more capillaries per villus, was identified in several areas within a placenta or more diffusely throughout the placental parenchyma uninvolved by dysplastic changes.[13] A 5-cm capillary chorioangioma was present in case 5 (Image 4D).

Figure 4.

Vascular changes in placental mesenchymal dysplasia. A, Case 8. Chorionic vessel with transmural necrosis and early fibrin thrombus (H&E, ×20). B, Case 6. Marked luminal stenosis of chorionic vessel with organizing intimal cushion (trichrome-elastin, ×20). C, Case 5. "Hemorrhagic endovasculitis" with endothelial cell damage, hemorrhage into vascular wall, and recanalization (H&E, ×100). D, Case 5. Capillary chorangioma (H&E, ×20).

Figure 4.

Vascular changes in placental mesenchymal dysplasia. A, Case 8. Chorionic vessel with transmural necrosis and early fibrin thrombus (H&E, ×20). B, Case 6. Marked luminal stenosis of chorionic vessel with organizing intimal cushion (trichrome-elastin, ×20). C, Case 5. "Hemorrhagic endovasculitis" with endothelial cell damage, hemorrhage into vascular wall, and recanalization (H&E, ×100). D, Case 5. Capillary chorangioma (H&E, ×20).

Figure 4.

Vascular changes in placental mesenchymal dysplasia. A, Case 8. Chorionic vessel with transmural necrosis and early fibrin thrombus (H&E, ×20). B, Case 6. Marked luminal stenosis of chorionic vessel with organizing intimal cushion (trichrome-elastin, ×20). C, Case 5. "Hemorrhagic endovasculitis" with endothelial cell damage, hemorrhage into vascular wall, and recanalization (H&E, ×100). D, Case 5. Capillary chorangioma (H&E, ×20).

Figure 4.

Vascular changes in placental mesenchymal dysplasia. A, Case 8. Chorionic vessel with transmural necrosis and early fibrin thrombus (H&E, ×20). B, Case 6. Marked luminal stenosis of chorionic vessel with organizing intimal cushion (trichrome-elastin, ×20). C, Case 5. "Hemorrhagic endovasculitis" with endothelial cell damage, hemorrhage into vascular wall, and recanalization (H&E, ×100). D, Case 5. Capillary chorangioma (H&E, ×20).

The placental parenchyma showed typical features of PMD. The stem villi were abnormally enlarged and often surrounded by excessive fibrinoid material. They consisted of a myxofibroblastic proliferation of spindle and stellate mesenchymal cells without cytologic atypia or prominent mitotic activity (Figure 5A), (Figure 5B), (Figure 5C), and (Figure 5D). The abundant extracellular matrix supporting the cells consisted primarily of hyaluronic acid, as demonstrated by a loss of alcian blue staining after hyaluronidase digestion. Villous stromal cystic degeneration, forming cisterns simulating those in molar villi, was present focally. Trophoblastic hyperplasia and inclusions were absent. Central thick-walled blood vessels with constricted lumens and scattered peripheral small capillaries were observed. Some vessels were thrombosed with recanalization. The residual normal placental villi showed maturation consistent with gestational ages. Excessive numbers of nucleated RBCs were identified in cases 3, 5, 7, and 9.

Figure 5.

Histology and immunohistochemistry of abnormal villi in placental mesenchymal dysplasia. A, Case 5. Enormous stem villi with excessive intervillous fibrinoid material and focal cistern formation (H&E, ×20). B, Case 10. Early cystic degeneration (H&E, ×20). C, Case 10. Central vessels with fibromuscular sclerosis (H&E, ×40). D, Case 6. Villous stromal cells with hyaluronic acid-rich extracellular matrix. Note peripheral capillaries (H&E, ×200). E, Case 5. Desmin strongly expressed in stromal cells of both normal and abnormal villi (×100). F, Case 5. Smooth muscle actin present in normal villous stromal cells but absent in abnormal villous stromal cells (×100).

Figure 5.

Histology and immunohistochemistry of abnormal villi in placental mesenchymal dysplasia. A, Case 5. Enormous stem villi with excessive intervillous fibrinoid material and focal cistern formation (H&E, ×20). B, Case 10. Early cystic degeneration (H&E, ×20). C, Case 10. Central vessels with fibromuscular sclerosis (H&E, ×40). D, Case 6. Villous stromal cells with hyaluronic acid-rich extracellular matrix. Note peripheral capillaries (H&E, ×200). E, Case 5. Desmin strongly expressed in stromal cells of both normal and abnormal villi (×100). F, Case 5. Smooth muscle actin present in normal villous stromal cells but absent in abnormal villous stromal cells (×100).

Figure 5.

Histology and immunohistochemistry of abnormal villi in placental mesenchymal dysplasia. A, Case 5. Enormous stem villi with excessive intervillous fibrinoid material and focal cistern formation (H&E, ×20). B, Case 10. Early cystic degeneration (H&E, ×20). C, Case 10. Central vessels with fibromuscular sclerosis (H&E, ×40). D, Case 6. Villous stromal cells with hyaluronic acid-rich extracellular matrix. Note peripheral capillaries (H&E, ×200). E, Case 5. Desmin strongly expressed in stromal cells of both normal and abnormal villi (×100). F, Case 5. Smooth muscle actin present in normal villous stromal cells but absent in abnormal villous stromal cells (×100).

Figure 5.

Histology and immunohistochemistry of abnormal villi in placental mesenchymal dysplasia. A, Case 5. Enormous stem villi with excessive intervillous fibrinoid material and focal cistern formation (H&E, ×20). B, Case 10. Early cystic degeneration (H&E, ×20). C, Case 10. Central vessels with fibromuscular sclerosis (H&E, ×40). D, Case 6. Villous stromal cells with hyaluronic acid-rich extracellular matrix. Note peripheral capillaries (H&E, ×200). E, Case 5. Desmin strongly expressed in stromal cells of both normal and abnormal villi (×100). F, Case 5. Smooth muscle actin present in normal villous stromal cells but absent in abnormal villous stromal cells (×100).

Figure 5.

Histology and immunohistochemistry of abnormal villi in placental mesenchymal dysplasia. A, Case 5. Enormous stem villi with excessive intervillous fibrinoid material and focal cistern formation (H&E, ×20). B, Case 10. Early cystic degeneration (H&E, ×20). C, Case 10. Central vessels with fibromuscular sclerosis (H&E, ×40). D, Case 6. Villous stromal cells with hyaluronic acid-rich extracellular matrix. Note peripheral capillaries (H&E, ×200). E, Case 5. Desmin strongly expressed in stromal cells of both normal and abnormal villi (×100). F, Case 5. Smooth muscle actin present in normal villous stromal cells but absent in abnormal villous stromal cells (×100).

Figure 5.

Histology and immunohistochemistry of abnormal villi in placental mesenchymal dysplasia. A, Case 5. Enormous stem villi with excessive intervillous fibrinoid material and focal cistern formation (H&E, ×20). B, Case 10. Early cystic degeneration (H&E, ×20). C, Case 10. Central vessels with fibromuscular sclerosis (H&E, ×40). D, Case 6. Villous stromal cells with hyaluronic acid-rich extracellular matrix. Note peripheral capillaries (H&E, ×200). E, Case 5. Desmin strongly expressed in stromal cells of both normal and abnormal villi (×100). F, Case 5. Smooth muscle actin present in normal villous stromal cells but absent in abnormal villous stromal cells (×100).

Immunohistochemical Findings

Immunohistochemically, stromal cells of normal and dysplastic villi were immunoreactive for desmin, similar to findings for an age-matched normal placenta. However, dysplastic villi were negative for smooth muscle actin, whereas normal villi were positive (Figure 5E) and (Figure 5F). There was no detectable Ki-67 or Flk-1 protein expression in either tissue. DNA ploidy analysis of the abnormal villi in case 5 demonstrated normal diploid constituency. Similarly, the abnormal villi in case 6 had a normal 46,XX karyotype, in accordance with the corresponding amniotic fluid.

Meta-analysis of IUGR and IUFD

Including the present cases, 82 cases of PMD have been reported ( Table 2 ).[1,2,3,4,5,6,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30] Of these cases, 15 were associated with an established or a probable diagnosis of BWS. Fetuses with BWS generally were larger than those without (mean ± SD, 79th ± 19th percentile vs 25th ± 26th percentile; P < .0001) (Figure 6). Similarly, fetuses with BWS had larger placentas than those without (mean ± SD, 3.9 ± 1.6 MoM vs 2.6 ± 1.3 MoM; P < .0093; normal placental weights referenced from established report).[9] Cases associated with BWS were excluded from the following analyses. Birth weight data and fetal outcome were available for 46 and 59 cases, respectively. The IUGR rate was 50% (23/46). The IUFD and neonatal death rates were 36% (21/59) and 7% (4/59), respectively. Of the deaths, 56% were not associated with IUGR (14 deaths without IUGR vs 11 deaths with concomitant IUGR). Females represented 82% (46/56) of the affected fetuses.

Figure 6.

Fetal birth weight distribution in placental mesenchymal dysplasia. BWS, Beckwith-Wiedemann syndrome.

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