Case of the Month: Uterus

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2016, case 20, and is placenta previa increta.

At the border between the placenta and the uterus, gross examination reveals stellate projections of placental tissue that extend into the uterine parenchyma. The placental tissue penetrates the endocervical stroma to a maximal depth of 1.0 cm and the lower uterine segment myometrium to within 0.4 cm of the serosa. Upon histological evaluation of the placental implantation site tissue, most of the decidua is absent. The chorionic villi extensively invade the myometrium. In most areas, the myometrium is separated from the chorionic villi by either a layer of fibrinoid variably infiltrated by extravillous trophoblast, by a layer of fibrinoid, or by extravillous trophoblast. In a few areas, the chorionic villi are adherent to the myometrium. Extravillous trophoblast (including a multinucleated giant cell component) is also noted extensively infiltrating the myometrium and involving the walls of some myometrial vessels. Other placental findings include the presence of patchy areas of accelerated villous maturation and villous stromal hemorrhage as well as focal intimal cellular proliferation noted on some stem villous vessels and chorionic plate vessels. The gross and microscopic findings identified in the lower uterine segment of the gravid uterus are consistent with a placenta previa increta.

Placenta previa is the result of implantation of the developing blastocyst in the lower uterine segment (LUS). In this setting, the placenta ends up partially or completely covering the internal os. Four types of placenta previa are defined in the literature: 

• Complete placenta previa: the placenta completely covers the internal os.
• Partial placenta previa: the placenta partially covers the internal os.
• Marginal placenta previa: the placenta reaches the internal os, but does not cover it.
• Low-lying placenta: the placenta extends into the lower uterine segment, but does not reach the internal os.

The incidence of placenta previa is between 0.3% and 0.5% of pregnancies. The etiology is not known; however, some investigators favor the theory that changes associated with prior scarring (due to surgery or trauma) are responsible for the LUS implantation. More than 90% of LUS implanted placentas identified early in pregnancy “move” away from the area as pregnancy progresses. Rather than placental “movement,” it is felt that the placenta grows toward a better vascularized area (the fundus); the placental parenchyma associated with the poorly vascularized area (the LUS/upper endocervix) undergoes atrophy. This process is referred to as trophotropism. In some instances, the areas of placental atrophy may leave viable blood vessels running (unsupported) through the fetal membranes. When these vessels cross or run in close proximity to the inner cervical os they are known as vasa previa and are at risk of rupture when the fetal membranes rupture. It is also felt that the development of the LUS as the result of the progression of the pregnancy also contributes to the “movement” of the placenta.

The classical clinical presentation of placenta previa is painless vaginal bleeding during the late second trimester or early third trimester of pregnancy. Pain and contractions may also be experienced. Risk factors for placenta previa include an abnormally shaped placenta (eg, bilobed placenta, succenturiate lobe), a large placenta, multiple fetuses, prior uterine surgery/scars (eg, Cesarean section [CS], myomectomy, endometrial curettage), maternal age of 35 years or older, multiparity, cocaine use, and a history of cigarette smoking. A prior history of placenta previa is also a risk factor (the recurrence rate is between 4% and 8%). Maternal morbidities include obstetrical hemorrhage (antepartum, intrapartum, and postpartum), abnormal placental implantation (eg, placenta accreta, increta, or percreta), abruption, septicemia, placental abruption, and death. Preterm birth, intrauterine growth restriction, intrauterine fetal demise, and a higher rate of congenital malformations can also be seen in association with placenta previa.

Most cases of placenta previa are diagnosed at the time of routine sonography during the second trimester; the majority of patients are asymptomatic. Transvaginal sonography is considered the imaging modality of choice when the diagnosis of placenta previa needs to be confirmed. The process is well tolerated, safe, and superior to transabdominal sonography. Patients with a diagnosis of placenta previa can be asymptomatic, actively bleeding, or stable after one or more episodes of active bleeding. Those that are asymptomatic are monitored in an outpatient setting; they are instructed to avoid excess physical activity and to call their health care provider promptly if bleeding or labor occurs. They undergo Cesarean delivery at 36 to 37 weeks of gestation if no complications arise. Patients with an actively bleeding placenta previa are hospitalized for close maternal and fetal monitoring and supportive care. If any significant obstetrical complications occur (eg, life threatening hemorrhage, non-reassuring fetal heart tones), they undergo CS. Patients that are stable after one or more episodes of active bleeding are monitored in an outpatient setting unless significant obstetrical complications arise.

Placenta previa is a clinical term. However, placentas examined following deliveries complicated by this abnormal presentation are usually disrupted and hemorrhagic. In some cases, most of the disc will be involved, while in others, only the margin of the disc will show pathological changes. It is not uncommon to find infarcted, hemorrhagic, and/or atrophic areas in the affected regions. In cases where uterine bleeding cannot be controlled, a hysterectomy may be clinically indicated. Depending on the gestational age and the extent of the obstetrical complications, the resected gravid uterus may reveal (in addition to the placenta) the presence of a gestational sac and a fetus. In addition to the examination of the fetus, the uterus, and the placenta, detailed gross and microscopic evaluation of the placental implantation site is necessary in order to exclude the presence of placenta accreta. The developmental features of the placenta and any pathological abnormalities (eg, velamentous insertion of the umbilical cord, the presence of a succenturiate lobe) should be noted. Examination of the fetus should be detailed; in addition to describing developmental characteristics, the fetus should be evaluated for the presence of congenital abnormalities.

As previously mentioned, there is an association between placenta previa, placenta accreta, and a prior history of uterine surgery, in particular CSs. According to the current literature, an increase in the rate of CSs is responsible for increases in the incidence of placenta previa and placenta accreta. Women who have had two or more CSs associated with placenta previa have nearly a 40% risk of developing placenta accreta. The prevalence of placenta accreta is difficult to determine due to the variations in clinicopathological definitions and local CS rates.

The general term placenta accreta describes an implantation process in which the placenta abnormally adheres to the uterine wall. This abnormal implantation is due to partial or total absence of the endometrium (affecting the normal development of the decidua). In this setting, there is deficient decidualization at the implantation site. Placenta accreta was the term widely used before imaging techniques were available to clinically assess depth of invasion at the implantation site, so it is still generally used to refer to all types of abnormally adherent placenta. However (as imaging technology improves) three terms are now used to further characterize this abnormal implantation process based on the depth of myometrial invasion: accreta, increta, and percreta. The term placenta accreta is used when the myometrial invasion is superficial. In cases of placenta increta there is deeper (more than superficial) myometrial invasion. In placenta percreta, the invasion penetrates through the myometrium extending to (or through) the serosa. Placenta increta and percreta are rare. The abnormal adherence may involve all of the cotyledons (total placenta accreta), one or more cotyledons - but not all (partial placenta accreta), or portions of lobes (focal placenta accreta).

According to the literature, it seems likely that the existence of decidua is necessary for the placenta to spontaneously separate from the myometrium; uterine contractions are likely responsible for this efficient separation. However, in the absence of properly developed decidua, uterine contractions are incapable of dislodging the placenta, resulting in retention of parts of the placenta or of the entire disc. When the decidua is not present, the trophoblast continues to invade the myometrium and the chorionic villi infiltrate the myometrium. According to the current literature, numerous regulatory molecules play functional roles in the process of “normal” decidualization and placental implantation. Studies demonstrating alterations in the “normal” interactions of many of these molecules (eg, VEGF, PIGF, E-cadherin) suggest changes that account for the development of abnormal placentation.

Conditions that affect the proper development of the decidua (eg, uterine anomalies, submucosal leiomyomas, scars due to prior uterine surgery) can predispose to placenta accreta. It is also important to remember that the endometrial linings of the uterine cornual regions and the LUS, as well as the mucosa of the upper endocervix, do not support the development of a decidual reaction capable of supporting the usual placental implantation. In addition, many of the risk factors for placenta accreta are similar to the risk factors for placenta previa (see previous section). In the presence of any of these risk factors, health care providers must have a high clinical suspicion for placenta accreta and take appropriate precautions.

Maternal morbidities include obstetrical hemorrhage that may require surgical intervention (eg, hysterectomy), adult respiratory distress syndrome, disseminated intravascular coagulation, spontaneous uterine rupture, and death. Preterm birth and intrauterine fetal demise can also be seen in association with placenta accreta. Most cases of placenta accreta are diagnosed by ultrasonography, occasionally supplemented by magnetic resonance imaging. Elevated maternal serum levels of alpha-fetoprotein can be identified in up to 45% of patients with placenta accreta. If a patient is suspected of having a placenta accreta, the recommended management is a planned preterm cesarean hysterectomy with the placenta left in situ (placental removal is associated with significant hemorrhage-related morbidity). However, other approaches need to be considered if the patient desires to preserve her fertility or if significant unexpected obstetrical complications develop.

When placenta accreta is clinically diagnosed or suspected, a liveborn baby (usually premature) and the placenta may be delivered if the obstetrical complications are not too serious. In these cases, the placenta may be the only specimen submitted for evaluation. The maternal surface is commonly disrupted and incomplete, or the specimen may be submitted in several parts (eg, a specimen submitted as “placenta” accompanied by a second specimen submitted as “uterine contents” – the result of an attempt to remove any retained products of conception). These disrupted placentas need to be carefully examined as they may have grossly evident areas of adherent myometrium on the maternal surface, hemorrhages, and infarcts in addition to other pathological features (eg, marginally inserted umbilical cord, circummarginate insertion of the extraplacental fetal membranes). In some cases, where the gross evaluation of a placenta is unremarkable for adherent myometrium, microscopic foci of myometrial tissue may be adherent to the basal plate with deficient intervening decidua, consistent with a mild or focal form of placenta accreta. These milder forms of placenta accreta (some of them not clinically suspected) are frequently associated with previous uterine surgery and multiparity, or may be submitted for evaluation due to a history of retained placental tissue or postpartum hemorrhage. Placental examination is useful in making the diagnosis of placenta accreta in cases not requiring hysterectomy, particularly when the basal plate is well sampled. On occasion, endometrial curettings of products of conception may have features consistent with these milder forms of placenta accreta. If necessary, immunohistochemical stains (eg, keratin, smooth muscle actin) can assist in highlighting the histopathological features.

Due to the serious complications associated with placenta accreta, it is not uncommon for a hysterectomy to take place. As with cases of placenta previa, depending on the gestational age and the obstetrical complications (including efforts to save the fetus) the resected gravid uterus may contain (in addition to the placenta) a gestational sac and a stillborn fetus. Remote CS scars (or other types of scars due to prior uterine surgery) may also be present. If the delivery is recent, a CS incision (recently sutured or open; vertical or horizontal), in addition to old CS scars, may be identified. The gravid uterus (and any products of conception still associated with it) should be examined in detail. It is not uncommon to be able to grossly identify the presence of placenta increta and percreta, when the placenta and/or uterus are grossly evaluated. Examination of the placental implantation site should include sections from the placental/myometrium interface and assessment of any pathological myometrial findings in that area (eg, thinning, perforation, serosal adhesions). Representative sections of any non-gestational pathological findings (eg, fibroids) should be submitted.

The key microscopic finding in cases of placenta accreta is the absence of decidua. Microscopic evaluation of the grossly suspected areas will reveal (more commonly) fibrinoid infiltrated by extravillous trophoblast between the chorionic villi and the myometrium and (less commonly) chorionic villi adherent to the myometrium (without intervening decidua). It is important not to confuse extravillous trophoblast with decidua; immunohistochemical stains for keratin may assist in differentiating between the keratin positive extravillous trophoblast and the keratin negative decidua. Other pathological placental findings include focal deficient physiologic conversion of maternal vessels and deficiency of placental septum formation. In some situations normal findings may be misinterpreted as features placenta accreta, including the presence of components of the placental implantation site (extravillous trophoblast and placental site giant cells invading the myometrium) in curettings and sections of smooth muscle occasionally adherent to the decidua following a vaginal birth after a CS.

1. In which of the following situations is the term placenta accreta used?
   1. When the abnormal placental implantation includes invasion of the myometrium that extends to (or through) the serosa
   2. When the abnormal placental implantation process includes deeper (more than superficial) myometrial invasion
   3. When the abnormal placental implantation process includes superficial myometrial invasion
   4. When there is abnormal placental adherence that may involve all of the cotyledons
   5. When there is placental adherence that involves one of the cotyledons
2. Which of the following is the key microscopic finding in cases of placenta accreta?
   1. The absence of decidua
   2. The deficiency of placental septum formation
   3. The exclusive presence of chorionic villi adherent to the myometrium (without intervening decidua)
   4. The exclusive presence of fibrinoid infiltrated by extravillous trophoblast between the chorionic villi and the myometrium
   5. The focal deficient physiologic conversion of maternal vessels
3. Which of the following mucosal uterine regions DO NOT support the development of a decidual reaction capable of supporting the usual placental implantation?
   1. Lower uterine segment, fundus
   2. Upper and lower endocervical canal, posterior fundus
   3. Upper endocervix, anterior fundus
   4. Uterine cornu, anterior and posterior fundus
   5. Uterine cornu, lower uterine segment, upper endocervix

1. Baergen RN. Chapter 3, Macroscopic Evaluation of the Second and Third Trimester Placenta, in: Manual of Pathology of the Human Placenta. Second edition. New York, NY: Springer Science and Business Media, Inc: 2011:192-199,216-217.
2. Benirschke K, Burton GJ, Baergen RN. Chapter 6: Nonvillous Parts and Trophoblast Invasion. In: Pathology of the Human Placenta. Sixth Edition., Berlin, Heidelberg, DK: Springer-Verlag; 2012:193.
3. Duzyj CM, Buhimschi IA, Motawea H, et al. The invasive phenotype of placenta accreta extravillous trophoblasts associates with loss of E-cadherin. Placenta. 2015;36(6):645-651.
4. Jacques SM, Qureshi F, Trent VS, Ramirez NC. Placenta accreta: mild cases diagnosed by placental examination. Int J Gynecol Pathol. 1996;15(1):28-33.
5. Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Appendix in: Placental Pathology. Atlas of Non Tumor Pathology, First Series, Fascicle 3. Washington DC: American Registry of Pathology in collaboration with the Armed Forces Institute of Pathology; 2004:49-53.
6. Oppenheimer L. Society of Obstetricians and Gynaecologists of Canada. Diagnosis and management of placenta previa. J Obstet Gynaecol Can. 2007;29(3):261-273.
7. Oyelese Y, Smulian JC. Placenta previa, placenta accreta, and vasa previa. Obstet Gynecol. 2006;107(4):927-941.
8. Placenta accreta. Committee Opinion No. 529. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2012;120:207–211.
9. Silver RM, Barbour KD. Placenta accreta spectrum: accreta, increta, and percreta. Obstet Gynecol Clin North Am. 2015;42(2):381-402.
10. Wehrum MJ, Buhimschi IA, Salafia C, et al. Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast. Am J Obstet Gynecol. 2011;204(5):411.

2016
Nilsa C. Ramirez, MD
Surgical Pathology Committee
Nationwide Children’s Hospital
Columbus, OH

1. When the abnormal placental implantation process includes superficial myometrial (c)
2. The absence of decidua (a)
3. Uterine cornu, lower uterine segment, upper endocervix (e)