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Evaluation of the prenatally diagnosed mass
Seminars in Fetal & Neonatal Medicine 17 (2012) 185e191
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Evaluation of the prenatally diagnosed mass Timothy C. Lee, Oluyinka O. Olutoye* Texas Children’s Fetal Center, Texas Children’s Hospital and Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6701 Fannin Street Suite 1210, Houston, TX 77030, USA
s u m m a r y Keywords: Fetal Mass Prenatal Tumor
With the advent of advanced imaging technologies, the field of prenatal diagnosis and counseling has grown rapidly. The use of fetal ultrasound and ultrafast magnetic resonance imaging has allowed for prenatal identification of structural anomalies as well as neoplasm. The differential diagnosis of a fetal mass is dependent upon its location and the tissue characteristics of the mass on imaging. The use of amniocentesis for chromosomal analysis and genetic testing for known tumor-related genetic abnormalities may aid in further refining the diagnosis. Herein we describe a general diagnostic algorithm for fetal masses based upon their location within the body and how the appropriate diagnostic modalities may be applied in the clinical setting. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Advances in technology over the past two decades have enhanced prenatal diagnosis. The use of high resolution imaging such as fetal magnetic resonance imaging (MRI), echocardiography (ECHO) and high resolution three- or four-dimensional ultrasound has allowed clinicians to identify a spectrum of diseases in the prenatal period.1,2 With these advances in technology, the role of the clinician is to determine whether there is any role for prenatal intervention, counsel the parents on possible pre- and postnatal interventions, guide and prepare for the timing of delivery and provide a reasonable level of expectations for the postnatal course.3 2. Fetal ultrasound Ultrasonography is an integral part of the obstetrical practice and is now routinely used for evaluation of the fetus. This imaging modality serves a number of roles, allowing the obstetrician to estimate gestational age and confirm the number of fetuses, to identify fetal malformations, to determine fetal viability and wellbeing, and to allow for fetal intervention. In most advanced countries, routine obstetrical ultrasound is obtained to evaluate for fetal anomalies as part of standard prenatal care. Ultrasound provides a real-time imaging modality that has no radiation exposure and low cost, but there can be significant variability in the detection of anomalies dependent on the skill and experience of the sonographer.4 Even with user variability, the role of ultrasound has
* Corresponding author. Tel.: þ1 832 822 3135. E-mail address: [email protected] (O.O. Olutoye). 1744-165X/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.008
continued to evolve in prenatal evaluation, and in experienced hands, ultrasound can detect up to 70% of fetal anomalies.5 This ability to detect fetal anomalies is also coupled with the relative safety of fetal ultrasound. To date, there has been no study that demonstrates any significant deleterious effect of ultrasound on the fetus.6 Long term follow-up on children exposed to fetal ultrasound also did not demonstrate any significant difference in overall school performance as these children became teenagers.7 Although a randomized trial of prenatal ultrasonographic screening, the RADIUS (routine antenatal diagnostic imaging with ultrasound) trial, showed no benefit in perinatal outcome8,9 or survival of anomalous fetuses,4 multidisciplinary counseling following the detection of these anomalies significantly impact the perinatal management.3 Overall, ultrasonography is a safe and cost-effective method to screen for fetal malformations. The availability and affordability of this imaging modality lends itself to be the first-line screening tool when it comes to evaluating a fetus.
3. Fetal MRI The advent of ultrafast fetal MRI has provided the clinician with an imaging modality that provides excellent tissue resolution with no ionizing radiation. MRI provides a large field of view and can provide anatomic information that may be missed by fetal ultrasound.1,2 Within the current body of literature, there has been no known adverse sequela to the fetus from MR imaging.10,11 However, per the United States Food and Drug Administration, the safety of fetal MRI has not yet been fully established and their recommendations are that it should not be used in the first trimester and that patients should have informed consent prior to proceeding.
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The earlier limitations of fetal MRI were due to the slow acquisition time. During the acquisition, the fetus had a large possibility of moving during the examination, thereby degrading the image quality. With the advent of the ultrafast MRI scanners, the artifact and image degradation has been significantly reduced.12 The images are acquired at 300e400 ms with a series of images obtained over a 20 s period. The entire examination is w30 min. No sedation of the mother or fetus is required with the ultrafast MRI scanners. The images are obtained in three planes: axial, coronal, and sagittal. The limitations of fetal MRI are no different than those of standard MRI scans. The absolute contraindication for fetal MRI is the presence of any electromagnetic foreign body in the mother. However, another impediment to MRI use is that pregnant patients may be unable to lie supine due to discomfort, and some patients are claustrophobic. 4. The fetus with a lump/mass Abnormalities detected in the fetus on imaging studies are diagnosed based on anatomy and tissue characteristics on imaging. Obtaining tissue for histopathological analysis is usually not an option although amniocentesis and genetic testing for targeted genes may be helpful (e.g. retinoblastoma). Lumps or masses noted in the fetus are therefore classified based on their anatomic location, and differential diagnoses are generated on the basis of these characteristics and knowledge of neonatal tumors. Lumps or masses diagnosed in the fetus tend to be of a relatively large size. However, with advances in imaging technology, even subtle lumps can now be detected in utero.13 Fetal solid tumors are rare and the prognosis depends on the size and location. The remainder of this section briefly discusses the masses based on their anatomic location on imaging. Sacrococcygeal tumors will be covered in more detail in subsequent chapters. 4.1. Brain and central nervous system Congenital brain tumors represent 0.5e1.9% of all brain tumors in the pediatric population14; they comprise 10% of all antenatally diagnosed tumors, following extracranial teratomas, neuroblastoma, and soft tissue tumors.15 The majority of congenital brain tumors are located in the supratentorial region which is in sharp distinction to the majority of pediatric brain tumors, which are infratentorial. The prognosis for congenital brain tumors is poor. Isaacs16 reported a large series of prenatally diagnosed tumors and reported that an antenatal diagnosis made prior to 30 weeks of gestation portended a worse outcome, with mortality rate as high as 96%. This very high mortality rate was most likely due to the intracranial mass effect and resultant severe hydrocephalus, leading to stillbirth and in-utero demise. The role of prenatal diagnosis in brain and CNS tumors has been essential in guiding prenatal and postnatal therapy. With the advent of ultrafast MRI, the ability to identify these lesions and obtain imaging characteristics to aid in the diagnosis has evolved considerably (Fig. 1). With intracranial lesions, there are some imaging findings that are characteristic of all brain tumors. One of the most common initial findings is polyhydramnios. Polyhydramnios is believed to result from decreased swallowing by the fetus from a hypothalamic dysfunction17e19 and may be detected on routine obstetrical examination. Once the diagnosis is suspected, ultrasound and MRI imaging may demonstrate macrocephaly and hydrocephalus. The hydrocephalus is from the compressive effect of the intracranial mass on the ventricular system and cerebrospinal fluid outflow. If the fetus has significant macrocephaly, the mother may need to have a cesarean section to
Fig. 1. Magnetic resonance image of a fetus with a large intracranial mass. Note the macrocephaly and hydrocephalus. The imaging characteristics of the heterogeneous mass (white arrow) are suggestive of an intracranial teratoma. (Courtesy of Dr Amy Mehollin-Ray, Texas Children’s Fetal Center.)
prevent dystocia and even intrapartum tumor rupture and exsanguination.20,21 The most common congenital brain tumor is the intracranial teratoma. This accounts for >50% of all reported congenital brain tumors.16 Other types of intracranial tumors include primitive neuroectodermal tumors, astrocytomas, glioblastoma multiforme, craniopharyngiomas, and choroid plexus lesions. Using MRI, the ability to distinguish tumor type has become more accurate; however, the imaging characteristics of tumor types have significant overlap. Of note, intracranial tumors often present with imaging characteristics that resemble intracranial hemorrhage and the resulting hydrocephalus from hemorrhage. The use of Doppler ultrasound may help to differentiate between hemorrhage and tumor since there will be no flow within an isolated intracranial hemorrhage. Brain tumors can also be accompanied by hemorrhage. The reported incidence of tumor hemorrhage has ranged from 14% to 18% when a tumor is seen on prenatal imaging.16 Therefore, any time a fetus is diagnosed with intracranial hemorrhage, a possible underlying brain lesion should also be suspected. Prenatal evaluation with the neurosurgeon, neurologist and oncologist will be helpful for perinatal management and counseling about the expectations and long term outcomes.
4.2. Face and neck tumors Fetal oral or neck tumors can be readily identified by ultrasonography or MRI. Differential diagnoses of neck masses include teratoma, lymphangioma, congenital goiter, thyroid tumors, thymic cyst, neuroblastoma or hamartomas. Bilateral, cystic neck lesions may be related to chromosomal or genetic abnormalities that can be confirmed by amniocentesis for chromosomal analysis. The most common lesions and those that grow to a substantial size are teratomas (Fig. 2) or lymphangiomas. The imaging characteristics may be helpful in distinguishing teratomas from lymphangiomas.1Teratomas tend to unilateral, displace surrounding tissue and compress the tracheo-esophageal complex. Lymphangiomas infiltrate and encase nearby structures and displace
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Fig. 2. Fetal magnetic resonance image of a large cervical teratoma (white arrow) with solid and cystic components. The mass is larger than the fetal head.
the tracheo-esophageal complex from its prevertebral location. Teratomas are highly vascular and can result in fetal hydrops from a high output cardiac failure. In-utero resection of the cervical teratoma can be performed in such cases.22 Neck tumors may result in limitation of fetal swallowing and polyhydramnios. When the trachea is sufficiently displaced or compressed, fetal airway obstruction can be anticipated at delivery. These fetuses benefit from the EXIT procedure (ex-utero intrapartum treatment).23 The EXIT procedure is a modified Cesarean section during which access to the fetal airway is accomplished while the fetus is still on placental support. During a well-performed EXIT procedure, continued flow of oxygen to the fetus via the placenta allows for up to 2 h to perform laryngoscopy, bronchoscopy, tracheostomy or even tumor resection to secure the airway prior to separating the fetus from the placenta.23 In some cases the hyperextension of the neck associated with a large cervical mass can result in the carina being pulled up into or above the thoracic inlet.24 Such fetuses have hypoplasia of the upper lobes of the lung and die from pulmonary hypoplasia despite successfully securing the airway during an EXIT procedure.24 Tumors emanating from the fetal mouth can be diagnosed early in gestation as a persistently open fetal mouth even before the tumor becomes apparent.25 Epignathic teratoma (Fig. 3) or epignathus is the term used for tumors arising from the palate in the region of Rathke’s pouch. These tumors may at times extend intracranially.25,26 Other teratomas can arise from the base of the tongue or tonsils. Congenital epulis arising from the alveolar ridge of the gums can also grow to considerable size. The prenatal concerns with these lesions include the limitation of swallowing and accompanying polyhydramnios that can result in preterm labor. In addition, large tumors can result in airway obstruction, prompting the need for delivery via an EXIT procedure. Whereas most of these lesions are benign and can be completely surgically excised, those with intracranial extension are more challenging and may require extensive maxillofacial reconstructive surgery. When diagnosed prenatally, fetuses with face, oral and cervical masses should be monitored for polyhydramnios and assessed for the potential for airway obstruction at birth. The degree of compression or displacement of the tracheo-esophageal complex may assist in identifying those at higher risk. Consultation with appropriate surgical and medical specialties and creation of
Fig. 3. Magnetic resonance image of a fetus with an epignathic teratoma (white arrow) protruding from and filling the mouth. (Courtesy of Dr Amy Mehollin-Ray, Texas Children’s Fetal Center.)
a delivery plan for high risk cases is crucial. As preterm labor frequently occurs with these conditions, the mother should have ready access to a facility capable of providing advanced perinatal airway management, including the EXIT procedure. 4.3. Tumors in the chest Thoracic masses can result in significant distortion of the thoracic anatomy. Differential diagnoses of thoracic masses include mediastinal tumors, lung masses, foregut duplication anomalies or herniated abdominal viscera due to a congenital diaphragmatic hernia. Careful ultrasound and MRI evaluation can help identify the tissue of origin or anatomic location.1 Echocardiography is helpful to assess the impact of the mass on cardiac function and also for evaluation of cardiac tumors. 4.3.1. Cardiac tumors Fetal cardiac tumors can be detected incidentally during echocardiography or may present with cardiomegaly, pericardial effusion, arrhythmias or evidence of heart failure. The tumors can be single or multiple. Multiple lesions tend to be rhabdomyomas that have a high association with tuberous sclerosis.27,28 In such cases, imaging of the fetal brain is warranted to evaluate for cerebral tubers and amniocentesis for genetic evaluation.29 Solitary lesions can be rhabdomyomas, teratomas or fibromas. Prenatal management is directed towards treatment of symptoms, if any. Antiarrhythmic agents may be used for symptomatic arrhythmias. Those whose tumors result in obstructive symptoms have a worse prognosis. Delivery should be in a facility able to manage any postnatal hemodynamic consequences that may result. Cardiac tumors may result in neonatal arrhythmias.30 Multiple rhabdomyomas may regress over time, leaving the neurological consequences of tuberous sclerosis as the dominant concern.31 Features of tuberous sclerosis may not be apparent in the fetal or neonatal periods, so patients with multiple cardiac rhabdomyomas should be followed long term.28
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4.3.2. Mediastinal tumors Fetal mediastinal masses are rare.13 When they occur, they are most commonly pericardial teratomas but can also be thymic cysts, intrathoracic goiter, neuroblastoma or foregut duplication cysts. The foregut or thymic cystic lesions are readily distinguished on imaging, and rarely cause any prenatal concerns.32 Mediastinal epicardial teratomas may grow to a considerable size and exert a mass effect on the heart. Restriction of cardiac function may result in fetal hydrops. Those who do not develop hydrops can be safely observed.33 Fetal intervention for drainage of a large pericardial effusion34 or in-utero resection of the teratoma33,35 may be indicated when hydrops is present. 4.3.3. Lung mass Masses in the fetal lung are being diagnosed with increasing frequency with advances in ultrasound technology and MRI resolution. The masses can appear cystic and/or solid (Fig. 4) and may or may not have a systemic vessel associated with them. Histologically, these lesions can be congenital cystic adenomatoid malformations (CCAMs), bronchopulmonary sequestration, bronchial atresia,36,37 congenital lobar emphysema,38 or rarely, pleuropulmonary blastoma39 or fetal lung interstitial tumor.40,41 The natural history of a fetal lung mass depends on the size of the mass and whether it exerts sufficient mass effect on the surrounding structures to result in any physiologic derangement.42 Large lung masses can compress the esophagus, limiting swallowing and resulting in polyhydramnios that can induce preterm labor. In addition, persistent compression of the adjacent lung tissue can cause pulmonary hypoplasia. If the mass sufficiently deviates and compresses the heart and impairs venous return to the heart, fetal heart failure (non-immune hydrops) may result. The period of rapid growth of lesions is between 18 and 26 weeks of gestation. After about 28 weeks, the growth of the fetus typically exceeds that of the mass. In the majority of cases, the mass actually regresses and may no longer be appreciated on prenatal sonograms. However, these ‘vanishing lesions’ are still evident on postnatal computerized tomograms.43 In some cases, the mass stays relatively large. In those cases where the mass is large enough to cause fetal hydrops, fetal intervention may be required. This includes percutaneous drainage of large
cystic lesions, insertion of thoracoamniotic shunts, or even fetal thoracotomy and lobectomy for solid masses.42,44,45 There is a correlation of the size of the mass with the propensity to develop fetal complications. In an attempt to standardize the measurement of the fetal lung masses, a CCAM:volume ratio (CVR) was described as a ratio of the volume of the mass and the head circumference of the fetus.46 In our experience, fetuses with a CVR >2.0 are at risk of in-utero complications.47 Anecdotal reports have suggested that maternal treatment with betametasone can limit the growth of these masses.48e50 Prospective randomized studies are required to determine whether steroid therapy is indeed efficacious or merely used coincidentally in lesions that would otherwise regress. Some of the masses remain large and occupy a significant portion of the thoracic cavity until term. Although these fetuses are asymptomatic in utero, the mass effect could significantly impair ventilation following delivery. Positive pressure ventilation may cause the masses to increase in size and further worsen the cardiac compression and lead to cardiovascular collapse. Such cases are better served with an exutero intrapartum treatment (EXIT-to-resection) where the mass is resected at the time of delivery while the fetus is still on placental support.44 The majority of fetuses with lung masses have an uneventful pregnancy and are asymptomatic after birth. Those that are symptomatic in the neonatal period should undergo surgical resection. Most of the masses are benign developmental anomalies. However, a rare form of pulmonary malignant neoplasm, pleuropulmonary blastoma, is almost indistinguishable from CCAM by current imaging modalities.39 This presents a diagnostic dilemma that must be discussed with the family during prenatal counseling. Lung masses with an unusual growth pattern are less likely to be developmental anomalies. Persistent growth of a lung mass into late gestation was noted in a case of fetal lung interstitial tumor.40 Extensive prenatal counseling about the different forms of lung masses, the natural history of these lesions and potential treatment options is required when a fetus presents with a mass in the lung. The character of the lesion during serial evaluation in utero can determine the potential for perinatal distress and help guide location and mode of delivery. 4.4. Tumors in the fetal abdomen
Fig. 4. Fetal magnetic resonance image showing a large heterogeneous, multicystic lung mass (white arrow). There was no associated systemic vessel.
4.4.1. Fetal adrenal mass Neuroblastoma is the most common fetal malignancy.14 The tumor arises from the sympathetic nervous system and therefore can present at any location along the course of sympathetic chain or the adrenal glands. Acharya et al. reported that the majority of neuroblastomas are identified after 32 weeks of gestation and that 93% were adrenal in origin.51 Maternal symptoms can often be a presenting symptom of a fetal neuroblastoma. In advanced cases, fetal catecholamines can reach the maternal circulation leading to maternal hypertension and even pre-eclampsia.52,53 When a suprarenal mass is identified on prenatal ultrasound, the differential diagnosis can be quite broad. Often adrenal hemorrhage can resemble a suprarenal mass. Adrenal hemorrhage is seen in the neonate and has also been reported late in gestation.54 A pulmonary extralobar sequestration (ELS) can also be present in this anatomic region.55 The ELS is most commonly supradiaphragmatic, but 10e15% may present within the suprarenal region.56 Curtis et al.57 developed a diagnostic algorithm to differentiate ELS and neuroblastoma based on prenatal ultrasound findings. They concluded that ELS was most often left-sided, solid, and more commonly identified in the second trimester whereas
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congenital neuroblastomas were more often right-sided, cystic in nature, and detected later in gestation.57 Currently, there is no fetal intervention indicated for fetal neuroblastoma. However, if there are fetal or maternal complications from the tumor, early delivery may be necessary. Tumors can be large enough to cause abdominal dystocia and fetal metastasis can also occur. Close monitoring during the pregnancy is warranted. 4.4.2. Liver mass Hepatic masses represent w5% of all congenital tumors.58 When a hepatic mass is identified, the most common primary hepatic tumor is an infantile hemangioendothelioma, followed by mesenchymal hamartoma and then hepatoblastoma.59 Liver lesions are typically diagnosed prenatally by ultrasound. Fetal MRI may allow differentiation of the tumor types and also provide more detailed imaging of the exact anatomy of the lesion. Infantile hemangioendotheliomas have been detected as early as 16 weeks of gestation. These lesions are often hypervascular with a heterogeneous appearance that consists of solid and cystic components. Calcifications can also be present on ultrasound.60 Due to the hypervascularity of these lesions, the fetus can develop high output cardiac failure and fetal hydrops.61,62 In addition, fetuses with these lesions may also develop KasabacheMerritt syndrome with concomitant anemia, thrombocytopenia and consumptive coagulopathy.63 One of the first-line therapies for treatment of high output cardiac failure is maternal corticosteroids, which may lead to regression of the lesion.64 Mesenchymal hamartomas are benign lesions of the liver. These lesions can often be confused with a hemangioendothelioma since they often are heterogeneous and have mixed solid and cystic components. One major imaging difference is that hamartomas do not have increased vascularity on fetal ultrasound.65 These lesions often do not have elevated maternal alpha-fetoprotein and betahuman chorionic gonadotropin.65 Furthermore, the lesions do enlarge during pregnancy and delivery by cesarean section may be indicated due to the size of the hepatic mass to avoid abdominal dystocia or intrapartum tumor rupture. Fetal mesenchymal hamartomas may be associated with placental mesenchymal dysplasia. The placental dysplasia may mimic a partial hydatidiform mole.66,67 Postnatal surgery is the only cure for these lesions; however, the surgery is often limited by the anatomic extension of the mass. Hepatoblastoma is the most common congenital malignancy of the liver. The prenatal imaging can demonstrate a solid, echogenic lesion with a capsule.68 These lesions do not have the hypervascularity seen in hemangioendothelioma but can present with calcifications and focal areas of tumor necrosis.68 The prognosis for these tumors is often very poor. The fetuses can present with polyhydramnios and non-immune fetal hydrops.69 Ammann et al.70 reported that out of seven cases diagnosed prenatally, six of the neonates died within 15 days of delivery. The risk of rupture is very high with these lesions, and in one small series, 80% of the infants delivered vaginally had tumor rupture.70 Therefore cesarean section should be recommended for mothers who have a fetus with a large hepatoblastoma.71 4.4.3. Renal mass Renal tumors of the fetus are rare findings with the most common prenatal renal anomalies being hydronephrosis and multicystic dysplastic kidneys. Hydronephrosis and multicystic kidneys appear cystic on fetal ultrasound and are easy to differentiate from solid tumors. The most common prenatally diagnosed solid renal tumor is a mesoblastic nephroma.72 On imaging the mesoblastic nephroma is indistinguishable from a Wilms’ tumor
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which can also be diagnosed prenatally. Fetal renal tumors may present as a solid homogeneous echogenic mass. One of the signs often leading to discovery of renal tumors is the presence of polyhydramnios. The exact etiology of polyhydramnios is unclear, but it has been suggested that it is related to increased renal blood flow or compression of the gastrointestinal tract from tumor mass effect.73,74 The polyhydramnios also predisposes the pregnancy to preterm delivery and the mothers should be so counseled. In a review of 28 prenatally diagnosed renal tumors, the median gestational age at birth was 35 weeks with 39% of the mothers presenting with polyhydramnios.75 Even though fetal MRI is insufficient to lead to the exact diagnosis, it does allow for improved delineation of the relationship of the tumor to adjacent structures and improved tissue contrast for the tumor itself.76 Furthermore, fetal MRI also allows for evaluation of the contralateral kidney for anomalies or synchronous masses. When cystic lesions are identified within the mass, the cystic areas are often due to tumor hemorrhage and necrosis. Fetuses with renal tumors should be carefully evaluated to rule out associated anomalies that may be present. Wilms’ tumor may be part of Perlman’s syndrome, signs of which include fetal ascites, hepatomegaly, macrosomia and polyhydramnios. A clear family history of Wilms’ tumor should be obtained. When the pregnancy approaches term, close ultrasound follow-up should be performed to assess the size of the mass. If possible, attempts at vaginal delivery should be made since these tumors seldom achieve a size that would preclude vaginal delivery. To date, no fetal intervention is indicated for management of renal tumors. 4.4.4. Ovarian mass The majority of masses in the pelvis in a female fetus are from the ovary. Most of these are cystic lesions that are follicular or lutein cysts. The majority of the cysts regress postnatally and do not require intervention. Solid or complex ovarian lesions may be teratomas. When diagnosed in the fetus, they tend to be immature teratomas and benefit from postnatal resection. Simple fetal ovarian cysts tend to be benign and most will regress. Those lesions >5 cm in size are at risk for torsion. Ovarian torsion can occur prenatally and the ovary and adnexa are amputated and resorb in utero. Persistent large lesions (>5 cm) remain at risk for postnatal torsion and should be followed closely. Ovarian cystectomy with preservation of ovarian tissue is the preferred treatment. Solid or complex lesions should undergo postnatal surgical excision for tissue diagnosis. Since many of these lesions are benign, immature teratomas, ovary-preserving techniques should be employed whenever possible. Other germ cell tumors and sacrococcygeal teratomas are discussed in more detail elsewhere in this issue of Seminars. 4.5. Retinoblastoma Retinoblastomas are tumors of the retina and are commonly diagnosed in children between the ages of 1 and 2 years.77 In those with a family history of retinoblastoma, prenatal genetic testing may be helpful to determine fetal genetic risk.78 However, retinoblastomas may develop in many children who do not have a family history of eye cancer. Local therapy can be curative for small lesions, thus early diagnosis is important. Ultrasound of the eye can be useful for early diagnosis. In fetuses at risk, based on a family history and/or confirmed genetic mutations, there are anecdotal reports of focused evaluation of the eye with very thin MRI slices being used to identify early lesions. Whether early delivery of such fetuses to allow for early treatment should even be considered is debatable. By the time the lesions are visible on prenatal imaging, the benefits of early diagnosis may already be lost.
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5. Conclusions Access to prenatal care and advances in prenatal imaging have allowed the identification of lesions and tumors within the fetus. The differential diagnoses of these lesions is based upon the anatomic location and imaging characteristics on imaging. Adjunctive genetic studies may further refine the list of differential diagnoses. Most of these lesions will not have untoward consequences in fetal life and may be amenable to treatment postnatally. In selected rare cases, prenatal intervention may be life-saving and/ or reduce perinatal morbidity.
Practice points Fetal ultrasound and MRI are complementary in defining tissue characteristics of prenatal tumors. Multidisciplinary counseling is beneficial. An understanding of the perinatal natural history of the lesion will guide timing, location and mode of delivery. Fetal intervention is indicated only in select, rare cases.
Conflict of interest statement None declared. Funding sources None. References 1. Santos XM, Papanna R, Johnson A, et al. The use of combined ultrasound and magnetic resonance imaging in the detection of fetal anomalies. Prenat Diagn 2010;30:402e7. 2. Nemec SF, Horcher E, Kasprian G, et al. Tumor disease and associated congenital abnormalities on prenatal MRI. Eur J Radiol 2012;81:e115e22. 3. Crombleholme TM, D’Alton M, Cendron M, et al. Prenatal diagnosis and the pediatric surgeon: the impact of prenatal consultation on perinatal management. J Pediatr Surg 1996;31:156e62. discussion 162e3. 4. Crane JP, LeFevre ML, Winborn RC, et al. A randomized trial of prenatal ultrasonographic screening: impact on the detection, management, and outcome of anomalous fetuses. The RADIUS Study Group. Am J Obstet Gynecol 1994;171:392e9. 5. VanDorsten JP, Hulsey TC, Newman RB, et al. Fetal anomaly detection by second-trimester ultrasonography in a tertiary center. Am J Obstet Gynecol 1998;178:742e9. 6. Kieler H, Ahlsten G, Haglund B, et al. Routine ultrasound screening in pregnancy and the children’s subsequent neurologic development. Obstet Gynecol 1998;91:750e6. 7. Stalberg K, Axelsson O, Haglund B, et al. Prenatal ultrasound exposure and children’s school performance at age 15e16: follow-up of a randomized controlled trial. Ultrasound Obstet Gynecol 2009;34:297e303. 8. LeFevre ML, Bain RP, Ewigman BG, et al. A randomized trial of prenatal ultrasonographic screening: impact on maternal management and outcome. RADIUS (Routine Antenatal Diagnostic Imaging with Ultrasound) Study Group. Am J Obstet Gynecol 1993;169:483e9. 9. Ewigman BG, Crane JP, Frigoletto FD, et al. Effect of prenatal ultrasound screening on perinatal outcome. RADIUS Study Group. N Engl J Med 1993;329:821e7. 10. Wolff S, James TL, Young GB, et al. Magnetic resonance imaging: absence of in vitro cytogenetic damage. Radiology 1985;155:163e5. 11. Baker PN, Johnson IR, Harvey PR, et al. A three-year follow-up of children imaged in utero with echo-planar magnetic resonance. Am J Obstet Gynecol 1994;170:32e3. 12. Brugger PC, Stuhr F, Lindner C, et al. Methods of fetal MR: beyond T2-weighted imaging. Eur J Radiol 2006;57:172e81. 13. Sbragia L, Paek BW, Feldstein VA, et al. Outcome of prenatally diagnosed solid fetal tumors. J Pediatr Surg 2001;36:1244e7. 14. Woodward PJ, Sohaey R, Kennedy A, et al. From the archives of the AFIP: a comprehensive review of fetal tumors with pathologic correlation. Radiographics 2005;25:215e42.
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J Pediatr Surg 2003;38:446e50. discussion 446e50. 23. Lazar DA, Olutoye OO, Moise Jr KJ, et al. Ex-utero intrapartum treatment procedure for giant neck masses e fetal and maternal outcomes. J Pediatr Surg 2011;46:817e22. 24. Liechty KW, Hedrick HL, Hubbard AM, et al. Severe pulmonary hypoplasia associated with giant cervical teratomas. J Pediatr Surg 2006;41:230e3. 25. Calda P, Novotna M, Cutka D, et al. A case of an epignathus with intracranial extension appearing as a persistently open mouth at 16 weeks and subsequently diagnosed at 20 weeks of gestation. J Clin Ultrasound 2011;39:164e8. 26. Cohen R, Nelson Jr MD, Segall HD. Epignathic teratoma associated with craniopharyngeal canal. Am J Neuroradiol 1989;10:652. 27. Saada J, Hadj Rabia S, Fermont L, et al. Prenatal diagnosis of cardiac rhabdomyomas: incidence of associated cerebral lesions of tuberous sclerosis complex. Ultrasound Obstet Gynecol 2009;34:155e9. 28. Atalay S, Aypar E, Ucar T, et al. Fetal and neonatal cardiac rhabdomyomas: clinical presentation, outcome and association with tuberous sclerosis complex. Turk J Pediatr 2010;52:481e7. 29. Milunsky A, Ito M, Maher TA, et al. Prenatal molecular diagnosis of tuberous sclerosis complex. Am J Obstet Gynecol 2009;200:321.e1e6. 30. De Rosa G, De Carolis MP, Pardeo M, et al. Neonatal emergencies associated with cardiac rhabdomyomas: an 8-year experience. Fetal Diagn Ther 2011;29:169e77. 31. Degueldre SC, Chockalingam P, Mivelaz Y, et al. Considerations for prenatal counselling of patients with cardiac rhabdomyomas based on their cardiac and neurologic outcomes. Cardiol Young 2010;20:18e24. 32. Kocaoglu M, Frush DP, Ugurel MS, et al. Bronchopulmonary foregut malformations presenting as mass lesions in children: spectrum of imaging findings. Diagn Interv Radiol 2010;16:153e61. 33. Merchant AM, Hedrick HL, Johnson MP, et al. Management of fetal mediastinal teratoma. J Pediatr Surg 2005;40:228e31. 34. Goldberg SP, Boston US, Turpin DA, et al. Surgical management of intrapericardial teratoma in the fetus. J Pediatr 2010;156. 848e9, 849.e1. 35. Sydorak RM, Kelly T, Feldstein VA, et al. Prenatal resection of a fetal pericardial teratoma. Fetal Diagn Ther 2002;17:281e5. 36. Kunisaki SM, Fauza DO, Nemes LP, et al. Bronchial atresia: the hidden pathology within a spectrum of prenatally diagnosed lung masses. J Pediatr Surg 2006;41:61e5. discussion 61e5. 37. Keswani SG, Crombleholme TM, Pawel BR, et al. Prenatal diagnosis and management of mainstem bronchial atresia. Fetal Diagn Ther 2005;20:74e8. 38. Olutoye OO, Coleman BG, Hubbard AM, et al. Prenatal diagnosis and management of congenital lobar emphysema. J Pediatr Surg 2000;35:792e5. 39. Miniati DN, Chintagumpala M, Langston C, et al. Prenatal presentation and outcome of children with pleuropulmonary blastoma. J Pediatr Surg 2006;41:66e71. 40. Lazar DA, Cass DL, Dishop MK, et al. Fetal lung interstitial tumor: a cause of late gestation fetal hydrops. J Pediatr Surg 2011;46:1263e6. 41. Dishop MK, McKay EM, Kreiger PA, et al. Fetal lung interstitial tumor (FLIT): a proposed newly recognized lung tumor of infancy to be differentiated from cystic pleuropulmonary blastoma and other developmental pulmonary lesions. Am J Surg Pathol 2010;34:1762e72. 42. Adzick NS. Management of fetal lung lesions. Clin Perinatol 2003;30:481e92. 43. Lee HJ, Song MJ, Cho JY, et al. Echogenic fetal lung masses: comparison of prenatal sonographic and postnatal CT findings. J Clin Ultrasound 2003;31:419e24. 44. Hedrick HL, Flake AW, Crombleholme TM, et al. The ex utero intrapartum therapy procedure for high-risk fetal lung lesions. J Pediatr Surg 2005;40:1038e43. discussion 1044. 45. Wilson RD, Baxter JK, Johnson MP, et al. Thoracoamniotic shunts: fetal treatment of pleural effusions and congenital cystic adenomatoid malformations. Fetal Diagn Ther 2004;19:413e20. 46. Crombleholme TM, Coleman B, Hedrick H, et al. Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung. J Pediatr Surg 2002;37:331e8. 47. Cass DL, Olutoye OO, Cassady CI, et al. Prenatal diagnosis and outcome of fetal lung masses. J Pediatr Surg 2011;46:292e8. 48. Peranteau WH, Wilson RD, Liechty KW, et al. Effect of maternal betamethasone administration on prenatal congenital cystic adenomatoid malformation growth and fetal survival. Fetal Diagn Ther 2007;22:365e71. 49. Morris LM, Lim FY, Livingston JC, et al. High-risk fetal congenital pulmonary airway malformations have a variable response to steroids. J Pediatr Surg 2009;44:60e5.
T.C. Lee, O.O. Olutoye / Seminars in Fetal & Neonatal Medicine 17 (2012) 185e191 50. Curran PF, Jelin EB, Rand L, et al. Prenatal steroids for microcystic congenital cystic adenomatoid malformations. J Pediatr Surg 2010;45:145e50. 51. Acharya S, Jayabose S, Kogan SJ, et al. Prenatally diagnosed neuroblastoma. Cancer 1997;80:304e10. 52. Jennings RW, LaQuaglia MP, Leong K, et al. Fetal neuroblastoma: prenatal diagnosis and natural history. J Pediatr Surg 1993;28:1168e74. 53. Lin JN, Lin GJ, Hung IJ, et al. Prenatally detected tumor mass in the adrenal gland. J Pediatr Surg 1999;34:1620e3. 54. Vollersen E, Hof M, Gembruch U. Prenatal sonographic diagnosis of fetal adrenal gland hemorrhage. Fetal Diagn Ther 1996;11:286e91. 55. Moon SB, Shin HB, Seo JM, et al. Clinical features and surgical outcome of a suprarenal mass detected before birth. Pediatr Surg Int 2010;26:241e6. 56. Chan YF, Oldfield R, Vogel S, et al. Pulmonary sequestration presenting as a prenatally detected suprarenal lesion in a neonate. J Pediatr Surg 2000;35:1367e9. 57. Curtis MR, Mooney DP, Vaccaro TJ, et al. Prenatal ultrasound characterization of the suprarenal mass: distinction between neuroblastoma and subdiaphragmatic extralobar pulmonary sequestration. J Ultrasound Med 1997;16:75e83. 58. Isaacs Jr H. Fetal and neonatal hepatic tumors. J Pediatr Surg 2007;42:1797e803. 59. Makin E, Davenport M. Fetal and neonatal liver tumours. Early Hum Dev 2010;86:637e42. 60. Roos JE, Pfiffner R, Stallmach T, et al. Infantile hemangioendothelioma. Radiographics 2003;23:1649e55. 61. Walton JM, Rubin SZ, Soucy P, et al. Fetal tumors associated with hydrops: the role of the pediatric surgeon. J Pediatr Surg 1993;28:1151e3. 62. Isaacs Jr H. Fetal hydrops associated with tumors. Am J Perinatol 2008;25:43e68. 63. Skopec LL, Lakatua DJ. Non-immune fetal hydrops with hepatic hemangioendothelioma and KasabacheMerritt syndrome: a case report. Pediatr Pathol 1989;9:87e93. 64. Morris J, Abbott J, Burrows P, et al. Antenatal diagnosis of fetal hepatic hemangioma treated with maternal corticosteroids. Obstet Gynecol 1999;94:813e5.
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65. Ruhland B, Schroer A, Gembruch U, et al. Prenatal imaging and postnatal pathologic work-up in a case of fetal hepatic hamartoma and placental mesenchymal dysplasia. Ultrasound Obstet Gynecol 2011;38:360e2. 66. Francis B, Hallam L, Kecskes Z, et al. Placental mesenchymal dysplasia associated with hepatic mesenchymal hamartoma in the newborn. Pediatr Dev Pathol 2007;10:50e4. 67. Carta M, Maresi E, Giuffre M, et al. Congenital hepatic mesenchymal hamartoma associated with mesenchymal stem villous hyperplasia of the placenta: case report. J Pediatr Surg 2005;40:e37e9. 68. Shih JC, Tsao PN, Huang SF, et al. Antenatal diagnosis of congenital hepatoblastoma in utero. Ultrasound Obstet Gynecol 2000;16:94e7. 69. Ergin H, Yildirim B, Dagdeviren E, et al. A prenatally detected case of congenital hepatoblastoma. Pathol Oncol Res 2008;14:97e100. 70. Ammann RA, Plaschkes J, Leibundgut K. Congenital hepatoblastoma: a distinct entity? Med Pediatr Oncol 1999;32:466e8. 71. Garmel SH, Crombleholme TM, Semple JP, et al. Prenatal diagnosis and management of fetal tumors. Semin Perinatol 1994;18:350e65. 72. Apuzzio JJ, Unwin W, Adhate A, et al. Prenatal diagnosis of fetal renal mesoblastic nephroma. Am J Obstet Gynecol 1986;154:636e7. 73. Geirsson RT, Ricketts NE, Taylor DJ, et al. Prenatal appearance of a mesoblastic nephroma associated with polyhydramnios. J Clin Ultrasound 1985;13:488e90. 74. Romano WL. Neonatal renal tumor with polyhydramnios. J Ultrasound Med 1984;3:475e6. 75. Leclair MD, El-Ghoneimi A, Audry G, et al. The outcome of prenatally diagnosed renal tumors. J Urol 2005;173:186e9. 76. Linam LE, Yu X, Calvo-Garcia MA, et al. Contribution of magnetic resonance imaging to prenatal differential diagnosis of renal tumors: report of two cases and review of the literature. Fetal Diagn Ther 2010;28:100e8. 77. Lohmann DR, Gallie BL. Retinoblastoma. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews. Seattle: University of Washington; 1993. 78. Xu K, Rosenwaks Z, Beaverson K, et al. Preimplantation genetic diagnosis for retinoblastoma: the first reported liveborn. Am J Ophthalmol 2004;137:18e23.
Contents lists available at SciVerse ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Evaluation of the prenatally diagnosed mass Timothy C. Lee, Oluyinka O. Olutoye* Texas Children’s Fetal Center, Texas Children’s Hospital and Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6701 Fannin Street Suite 1210, Houston, TX 77030, USA
s u m m a r y Keywords: Fetal Mass Prenatal Tumor
With the advent of advanced imaging technologies, the field of prenatal diagnosis and counseling has grown rapidly. The use of fetal ultrasound and ultrafast magnetic resonance imaging has allowed for prenatal identification of structural anomalies as well as neoplasm. The differential diagnosis of a fetal mass is dependent upon its location and the tissue characteristics of the mass on imaging. The use of amniocentesis for chromosomal analysis and genetic testing for known tumor-related genetic abnormalities may aid in further refining the diagnosis. Herein we describe a general diagnostic algorithm for fetal masses based upon their location within the body and how the appropriate diagnostic modalities may be applied in the clinical setting. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Advances in technology over the past two decades have enhanced prenatal diagnosis. The use of high resolution imaging such as fetal magnetic resonance imaging (MRI), echocardiography (ECHO) and high resolution three- or four-dimensional ultrasound has allowed clinicians to identify a spectrum of diseases in the prenatal period.1,2 With these advances in technology, the role of the clinician is to determine whether there is any role for prenatal intervention, counsel the parents on possible pre- and postnatal interventions, guide and prepare for the timing of delivery and provide a reasonable level of expectations for the postnatal course.3 2. Fetal ultrasound Ultrasonography is an integral part of the obstetrical practice and is now routinely used for evaluation of the fetus. This imaging modality serves a number of roles, allowing the obstetrician to estimate gestational age and confirm the number of fetuses, to identify fetal malformations, to determine fetal viability and wellbeing, and to allow for fetal intervention. In most advanced countries, routine obstetrical ultrasound is obtained to evaluate for fetal anomalies as part of standard prenatal care. Ultrasound provides a real-time imaging modality that has no radiation exposure and low cost, but there can be significant variability in the detection of anomalies dependent on the skill and experience of the sonographer.4 Even with user variability, the role of ultrasound has
* Corresponding author. Tel.: þ1 832 822 3135. E-mail address: [email protected] (O.O. Olutoye). 1744-165X/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.008
continued to evolve in prenatal evaluation, and in experienced hands, ultrasound can detect up to 70% of fetal anomalies.5 This ability to detect fetal anomalies is also coupled with the relative safety of fetal ultrasound. To date, there has been no study that demonstrates any significant deleterious effect of ultrasound on the fetus.6 Long term follow-up on children exposed to fetal ultrasound also did not demonstrate any significant difference in overall school performance as these children became teenagers.7 Although a randomized trial of prenatal ultrasonographic screening, the RADIUS (routine antenatal diagnostic imaging with ultrasound) trial, showed no benefit in perinatal outcome8,9 or survival of anomalous fetuses,4 multidisciplinary counseling following the detection of these anomalies significantly impact the perinatal management.3 Overall, ultrasonography is a safe and cost-effective method to screen for fetal malformations. The availability and affordability of this imaging modality lends itself to be the first-line screening tool when it comes to evaluating a fetus.
3. Fetal MRI The advent of ultrafast fetal MRI has provided the clinician with an imaging modality that provides excellent tissue resolution with no ionizing radiation. MRI provides a large field of view and can provide anatomic information that may be missed by fetal ultrasound.1,2 Within the current body of literature, there has been no known adverse sequela to the fetus from MR imaging.10,11 However, per the United States Food and Drug Administration, the safety of fetal MRI has not yet been fully established and their recommendations are that it should not be used in the first trimester and that patients should have informed consent prior to proceeding.
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The earlier limitations of fetal MRI were due to the slow acquisition time. During the acquisition, the fetus had a large possibility of moving during the examination, thereby degrading the image quality. With the advent of the ultrafast MRI scanners, the artifact and image degradation has been significantly reduced.12 The images are acquired at 300e400 ms with a series of images obtained over a 20 s period. The entire examination is w30 min. No sedation of the mother or fetus is required with the ultrafast MRI scanners. The images are obtained in three planes: axial, coronal, and sagittal. The limitations of fetal MRI are no different than those of standard MRI scans. The absolute contraindication for fetal MRI is the presence of any electromagnetic foreign body in the mother. However, another impediment to MRI use is that pregnant patients may be unable to lie supine due to discomfort, and some patients are claustrophobic. 4. The fetus with a lump/mass Abnormalities detected in the fetus on imaging studies are diagnosed based on anatomy and tissue characteristics on imaging. Obtaining tissue for histopathological analysis is usually not an option although amniocentesis and genetic testing for targeted genes may be helpful (e.g. retinoblastoma). Lumps or masses noted in the fetus are therefore classified based on their anatomic location, and differential diagnoses are generated on the basis of these characteristics and knowledge of neonatal tumors. Lumps or masses diagnosed in the fetus tend to be of a relatively large size. However, with advances in imaging technology, even subtle lumps can now be detected in utero.13 Fetal solid tumors are rare and the prognosis depends on the size and location. The remainder of this section briefly discusses the masses based on their anatomic location on imaging. Sacrococcygeal tumors will be covered in more detail in subsequent chapters. 4.1. Brain and central nervous system Congenital brain tumors represent 0.5e1.9% of all brain tumors in the pediatric population14; they comprise 10% of all antenatally diagnosed tumors, following extracranial teratomas, neuroblastoma, and soft tissue tumors.15 The majority of congenital brain tumors are located in the supratentorial region which is in sharp distinction to the majority of pediatric brain tumors, which are infratentorial. The prognosis for congenital brain tumors is poor. Isaacs16 reported a large series of prenatally diagnosed tumors and reported that an antenatal diagnosis made prior to 30 weeks of gestation portended a worse outcome, with mortality rate as high as 96%. This very high mortality rate was most likely due to the intracranial mass effect and resultant severe hydrocephalus, leading to stillbirth and in-utero demise. The role of prenatal diagnosis in brain and CNS tumors has been essential in guiding prenatal and postnatal therapy. With the advent of ultrafast MRI, the ability to identify these lesions and obtain imaging characteristics to aid in the diagnosis has evolved considerably (Fig. 1). With intracranial lesions, there are some imaging findings that are characteristic of all brain tumors. One of the most common initial findings is polyhydramnios. Polyhydramnios is believed to result from decreased swallowing by the fetus from a hypothalamic dysfunction17e19 and may be detected on routine obstetrical examination. Once the diagnosis is suspected, ultrasound and MRI imaging may demonstrate macrocephaly and hydrocephalus. The hydrocephalus is from the compressive effect of the intracranial mass on the ventricular system and cerebrospinal fluid outflow. If the fetus has significant macrocephaly, the mother may need to have a cesarean section to
Fig. 1. Magnetic resonance image of a fetus with a large intracranial mass. Note the macrocephaly and hydrocephalus. The imaging characteristics of the heterogeneous mass (white arrow) are suggestive of an intracranial teratoma. (Courtesy of Dr Amy Mehollin-Ray, Texas Children’s Fetal Center.)
prevent dystocia and even intrapartum tumor rupture and exsanguination.20,21 The most common congenital brain tumor is the intracranial teratoma. This accounts for >50% of all reported congenital brain tumors.16 Other types of intracranial tumors include primitive neuroectodermal tumors, astrocytomas, glioblastoma multiforme, craniopharyngiomas, and choroid plexus lesions. Using MRI, the ability to distinguish tumor type has become more accurate; however, the imaging characteristics of tumor types have significant overlap. Of note, intracranial tumors often present with imaging characteristics that resemble intracranial hemorrhage and the resulting hydrocephalus from hemorrhage. The use of Doppler ultrasound may help to differentiate between hemorrhage and tumor since there will be no flow within an isolated intracranial hemorrhage. Brain tumors can also be accompanied by hemorrhage. The reported incidence of tumor hemorrhage has ranged from 14% to 18% when a tumor is seen on prenatal imaging.16 Therefore, any time a fetus is diagnosed with intracranial hemorrhage, a possible underlying brain lesion should also be suspected. Prenatal evaluation with the neurosurgeon, neurologist and oncologist will be helpful for perinatal management and counseling about the expectations and long term outcomes.
4.2. Face and neck tumors Fetal oral or neck tumors can be readily identified by ultrasonography or MRI. Differential diagnoses of neck masses include teratoma, lymphangioma, congenital goiter, thyroid tumors, thymic cyst, neuroblastoma or hamartomas. Bilateral, cystic neck lesions may be related to chromosomal or genetic abnormalities that can be confirmed by amniocentesis for chromosomal analysis. The most common lesions and those that grow to a substantial size are teratomas (Fig. 2) or lymphangiomas. The imaging characteristics may be helpful in distinguishing teratomas from lymphangiomas.1Teratomas tend to unilateral, displace surrounding tissue and compress the tracheo-esophageal complex. Lymphangiomas infiltrate and encase nearby structures and displace
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Fig. 2. Fetal magnetic resonance image of a large cervical teratoma (white arrow) with solid and cystic components. The mass is larger than the fetal head.
the tracheo-esophageal complex from its prevertebral location. Teratomas are highly vascular and can result in fetal hydrops from a high output cardiac failure. In-utero resection of the cervical teratoma can be performed in such cases.22 Neck tumors may result in limitation of fetal swallowing and polyhydramnios. When the trachea is sufficiently displaced or compressed, fetal airway obstruction can be anticipated at delivery. These fetuses benefit from the EXIT procedure (ex-utero intrapartum treatment).23 The EXIT procedure is a modified Cesarean section during which access to the fetal airway is accomplished while the fetus is still on placental support. During a well-performed EXIT procedure, continued flow of oxygen to the fetus via the placenta allows for up to 2 h to perform laryngoscopy, bronchoscopy, tracheostomy or even tumor resection to secure the airway prior to separating the fetus from the placenta.23 In some cases the hyperextension of the neck associated with a large cervical mass can result in the carina being pulled up into or above the thoracic inlet.24 Such fetuses have hypoplasia of the upper lobes of the lung and die from pulmonary hypoplasia despite successfully securing the airway during an EXIT procedure.24 Tumors emanating from the fetal mouth can be diagnosed early in gestation as a persistently open fetal mouth even before the tumor becomes apparent.25 Epignathic teratoma (Fig. 3) or epignathus is the term used for tumors arising from the palate in the region of Rathke’s pouch. These tumors may at times extend intracranially.25,26 Other teratomas can arise from the base of the tongue or tonsils. Congenital epulis arising from the alveolar ridge of the gums can also grow to considerable size. The prenatal concerns with these lesions include the limitation of swallowing and accompanying polyhydramnios that can result in preterm labor. In addition, large tumors can result in airway obstruction, prompting the need for delivery via an EXIT procedure. Whereas most of these lesions are benign and can be completely surgically excised, those with intracranial extension are more challenging and may require extensive maxillofacial reconstructive surgery. When diagnosed prenatally, fetuses with face, oral and cervical masses should be monitored for polyhydramnios and assessed for the potential for airway obstruction at birth. The degree of compression or displacement of the tracheo-esophageal complex may assist in identifying those at higher risk. Consultation with appropriate surgical and medical specialties and creation of
Fig. 3. Magnetic resonance image of a fetus with an epignathic teratoma (white arrow) protruding from and filling the mouth. (Courtesy of Dr Amy Mehollin-Ray, Texas Children’s Fetal Center.)
a delivery plan for high risk cases is crucial. As preterm labor frequently occurs with these conditions, the mother should have ready access to a facility capable of providing advanced perinatal airway management, including the EXIT procedure. 4.3. Tumors in the chest Thoracic masses can result in significant distortion of the thoracic anatomy. Differential diagnoses of thoracic masses include mediastinal tumors, lung masses, foregut duplication anomalies or herniated abdominal viscera due to a congenital diaphragmatic hernia. Careful ultrasound and MRI evaluation can help identify the tissue of origin or anatomic location.1 Echocardiography is helpful to assess the impact of the mass on cardiac function and also for evaluation of cardiac tumors. 4.3.1. Cardiac tumors Fetal cardiac tumors can be detected incidentally during echocardiography or may present with cardiomegaly, pericardial effusion, arrhythmias or evidence of heart failure. The tumors can be single or multiple. Multiple lesions tend to be rhabdomyomas that have a high association with tuberous sclerosis.27,28 In such cases, imaging of the fetal brain is warranted to evaluate for cerebral tubers and amniocentesis for genetic evaluation.29 Solitary lesions can be rhabdomyomas, teratomas or fibromas. Prenatal management is directed towards treatment of symptoms, if any. Antiarrhythmic agents may be used for symptomatic arrhythmias. Those whose tumors result in obstructive symptoms have a worse prognosis. Delivery should be in a facility able to manage any postnatal hemodynamic consequences that may result. Cardiac tumors may result in neonatal arrhythmias.30 Multiple rhabdomyomas may regress over time, leaving the neurological consequences of tuberous sclerosis as the dominant concern.31 Features of tuberous sclerosis may not be apparent in the fetal or neonatal periods, so patients with multiple cardiac rhabdomyomas should be followed long term.28
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4.3.2. Mediastinal tumors Fetal mediastinal masses are rare.13 When they occur, they are most commonly pericardial teratomas but can also be thymic cysts, intrathoracic goiter, neuroblastoma or foregut duplication cysts. The foregut or thymic cystic lesions are readily distinguished on imaging, and rarely cause any prenatal concerns.32 Mediastinal epicardial teratomas may grow to a considerable size and exert a mass effect on the heart. Restriction of cardiac function may result in fetal hydrops. Those who do not develop hydrops can be safely observed.33 Fetal intervention for drainage of a large pericardial effusion34 or in-utero resection of the teratoma33,35 may be indicated when hydrops is present. 4.3.3. Lung mass Masses in the fetal lung are being diagnosed with increasing frequency with advances in ultrasound technology and MRI resolution. The masses can appear cystic and/or solid (Fig. 4) and may or may not have a systemic vessel associated with them. Histologically, these lesions can be congenital cystic adenomatoid malformations (CCAMs), bronchopulmonary sequestration, bronchial atresia,36,37 congenital lobar emphysema,38 or rarely, pleuropulmonary blastoma39 or fetal lung interstitial tumor.40,41 The natural history of a fetal lung mass depends on the size of the mass and whether it exerts sufficient mass effect on the surrounding structures to result in any physiologic derangement.42 Large lung masses can compress the esophagus, limiting swallowing and resulting in polyhydramnios that can induce preterm labor. In addition, persistent compression of the adjacent lung tissue can cause pulmonary hypoplasia. If the mass sufficiently deviates and compresses the heart and impairs venous return to the heart, fetal heart failure (non-immune hydrops) may result. The period of rapid growth of lesions is between 18 and 26 weeks of gestation. After about 28 weeks, the growth of the fetus typically exceeds that of the mass. In the majority of cases, the mass actually regresses and may no longer be appreciated on prenatal sonograms. However, these ‘vanishing lesions’ are still evident on postnatal computerized tomograms.43 In some cases, the mass stays relatively large. In those cases where the mass is large enough to cause fetal hydrops, fetal intervention may be required. This includes percutaneous drainage of large
cystic lesions, insertion of thoracoamniotic shunts, or even fetal thoracotomy and lobectomy for solid masses.42,44,45 There is a correlation of the size of the mass with the propensity to develop fetal complications. In an attempt to standardize the measurement of the fetal lung masses, a CCAM:volume ratio (CVR) was described as a ratio of the volume of the mass and the head circumference of the fetus.46 In our experience, fetuses with a CVR >2.0 are at risk of in-utero complications.47 Anecdotal reports have suggested that maternal treatment with betametasone can limit the growth of these masses.48e50 Prospective randomized studies are required to determine whether steroid therapy is indeed efficacious or merely used coincidentally in lesions that would otherwise regress. Some of the masses remain large and occupy a significant portion of the thoracic cavity until term. Although these fetuses are asymptomatic in utero, the mass effect could significantly impair ventilation following delivery. Positive pressure ventilation may cause the masses to increase in size and further worsen the cardiac compression and lead to cardiovascular collapse. Such cases are better served with an exutero intrapartum treatment (EXIT-to-resection) where the mass is resected at the time of delivery while the fetus is still on placental support.44 The majority of fetuses with lung masses have an uneventful pregnancy and are asymptomatic after birth. Those that are symptomatic in the neonatal period should undergo surgical resection. Most of the masses are benign developmental anomalies. However, a rare form of pulmonary malignant neoplasm, pleuropulmonary blastoma, is almost indistinguishable from CCAM by current imaging modalities.39 This presents a diagnostic dilemma that must be discussed with the family during prenatal counseling. Lung masses with an unusual growth pattern are less likely to be developmental anomalies. Persistent growth of a lung mass into late gestation was noted in a case of fetal lung interstitial tumor.40 Extensive prenatal counseling about the different forms of lung masses, the natural history of these lesions and potential treatment options is required when a fetus presents with a mass in the lung. The character of the lesion during serial evaluation in utero can determine the potential for perinatal distress and help guide location and mode of delivery. 4.4. Tumors in the fetal abdomen
Fig. 4. Fetal magnetic resonance image showing a large heterogeneous, multicystic lung mass (white arrow). There was no associated systemic vessel.
4.4.1. Fetal adrenal mass Neuroblastoma is the most common fetal malignancy.14 The tumor arises from the sympathetic nervous system and therefore can present at any location along the course of sympathetic chain or the adrenal glands. Acharya et al. reported that the majority of neuroblastomas are identified after 32 weeks of gestation and that 93% were adrenal in origin.51 Maternal symptoms can often be a presenting symptom of a fetal neuroblastoma. In advanced cases, fetal catecholamines can reach the maternal circulation leading to maternal hypertension and even pre-eclampsia.52,53 When a suprarenal mass is identified on prenatal ultrasound, the differential diagnosis can be quite broad. Often adrenal hemorrhage can resemble a suprarenal mass. Adrenal hemorrhage is seen in the neonate and has also been reported late in gestation.54 A pulmonary extralobar sequestration (ELS) can also be present in this anatomic region.55 The ELS is most commonly supradiaphragmatic, but 10e15% may present within the suprarenal region.56 Curtis et al.57 developed a diagnostic algorithm to differentiate ELS and neuroblastoma based on prenatal ultrasound findings. They concluded that ELS was most often left-sided, solid, and more commonly identified in the second trimester whereas
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congenital neuroblastomas were more often right-sided, cystic in nature, and detected later in gestation.57 Currently, there is no fetal intervention indicated for fetal neuroblastoma. However, if there are fetal or maternal complications from the tumor, early delivery may be necessary. Tumors can be large enough to cause abdominal dystocia and fetal metastasis can also occur. Close monitoring during the pregnancy is warranted. 4.4.2. Liver mass Hepatic masses represent w5% of all congenital tumors.58 When a hepatic mass is identified, the most common primary hepatic tumor is an infantile hemangioendothelioma, followed by mesenchymal hamartoma and then hepatoblastoma.59 Liver lesions are typically diagnosed prenatally by ultrasound. Fetal MRI may allow differentiation of the tumor types and also provide more detailed imaging of the exact anatomy of the lesion. Infantile hemangioendotheliomas have been detected as early as 16 weeks of gestation. These lesions are often hypervascular with a heterogeneous appearance that consists of solid and cystic components. Calcifications can also be present on ultrasound.60 Due to the hypervascularity of these lesions, the fetus can develop high output cardiac failure and fetal hydrops.61,62 In addition, fetuses with these lesions may also develop KasabacheMerritt syndrome with concomitant anemia, thrombocytopenia and consumptive coagulopathy.63 One of the first-line therapies for treatment of high output cardiac failure is maternal corticosteroids, which may lead to regression of the lesion.64 Mesenchymal hamartomas are benign lesions of the liver. These lesions can often be confused with a hemangioendothelioma since they often are heterogeneous and have mixed solid and cystic components. One major imaging difference is that hamartomas do not have increased vascularity on fetal ultrasound.65 These lesions often do not have elevated maternal alpha-fetoprotein and betahuman chorionic gonadotropin.65 Furthermore, the lesions do enlarge during pregnancy and delivery by cesarean section may be indicated due to the size of the hepatic mass to avoid abdominal dystocia or intrapartum tumor rupture. Fetal mesenchymal hamartomas may be associated with placental mesenchymal dysplasia. The placental dysplasia may mimic a partial hydatidiform mole.66,67 Postnatal surgery is the only cure for these lesions; however, the surgery is often limited by the anatomic extension of the mass. Hepatoblastoma is the most common congenital malignancy of the liver. The prenatal imaging can demonstrate a solid, echogenic lesion with a capsule.68 These lesions do not have the hypervascularity seen in hemangioendothelioma but can present with calcifications and focal areas of tumor necrosis.68 The prognosis for these tumors is often very poor. The fetuses can present with polyhydramnios and non-immune fetal hydrops.69 Ammann et al.70 reported that out of seven cases diagnosed prenatally, six of the neonates died within 15 days of delivery. The risk of rupture is very high with these lesions, and in one small series, 80% of the infants delivered vaginally had tumor rupture.70 Therefore cesarean section should be recommended for mothers who have a fetus with a large hepatoblastoma.71 4.4.3. Renal mass Renal tumors of the fetus are rare findings with the most common prenatal renal anomalies being hydronephrosis and multicystic dysplastic kidneys. Hydronephrosis and multicystic kidneys appear cystic on fetal ultrasound and are easy to differentiate from solid tumors. The most common prenatally diagnosed solid renal tumor is a mesoblastic nephroma.72 On imaging the mesoblastic nephroma is indistinguishable from a Wilms’ tumor
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which can also be diagnosed prenatally. Fetal renal tumors may present as a solid homogeneous echogenic mass. One of the signs often leading to discovery of renal tumors is the presence of polyhydramnios. The exact etiology of polyhydramnios is unclear, but it has been suggested that it is related to increased renal blood flow or compression of the gastrointestinal tract from tumor mass effect.73,74 The polyhydramnios also predisposes the pregnancy to preterm delivery and the mothers should be so counseled. In a review of 28 prenatally diagnosed renal tumors, the median gestational age at birth was 35 weeks with 39% of the mothers presenting with polyhydramnios.75 Even though fetal MRI is insufficient to lead to the exact diagnosis, it does allow for improved delineation of the relationship of the tumor to adjacent structures and improved tissue contrast for the tumor itself.76 Furthermore, fetal MRI also allows for evaluation of the contralateral kidney for anomalies or synchronous masses. When cystic lesions are identified within the mass, the cystic areas are often due to tumor hemorrhage and necrosis. Fetuses with renal tumors should be carefully evaluated to rule out associated anomalies that may be present. Wilms’ tumor may be part of Perlman’s syndrome, signs of which include fetal ascites, hepatomegaly, macrosomia and polyhydramnios. A clear family history of Wilms’ tumor should be obtained. When the pregnancy approaches term, close ultrasound follow-up should be performed to assess the size of the mass. If possible, attempts at vaginal delivery should be made since these tumors seldom achieve a size that would preclude vaginal delivery. To date, no fetal intervention is indicated for management of renal tumors. 4.4.4. Ovarian mass The majority of masses in the pelvis in a female fetus are from the ovary. Most of these are cystic lesions that are follicular or lutein cysts. The majority of the cysts regress postnatally and do not require intervention. Solid or complex ovarian lesions may be teratomas. When diagnosed in the fetus, they tend to be immature teratomas and benefit from postnatal resection. Simple fetal ovarian cysts tend to be benign and most will regress. Those lesions >5 cm in size are at risk for torsion. Ovarian torsion can occur prenatally and the ovary and adnexa are amputated and resorb in utero. Persistent large lesions (>5 cm) remain at risk for postnatal torsion and should be followed closely. Ovarian cystectomy with preservation of ovarian tissue is the preferred treatment. Solid or complex lesions should undergo postnatal surgical excision for tissue diagnosis. Since many of these lesions are benign, immature teratomas, ovary-preserving techniques should be employed whenever possible. Other germ cell tumors and sacrococcygeal teratomas are discussed in more detail elsewhere in this issue of Seminars. 4.5. Retinoblastoma Retinoblastomas are tumors of the retina and are commonly diagnosed in children between the ages of 1 and 2 years.77 In those with a family history of retinoblastoma, prenatal genetic testing may be helpful to determine fetal genetic risk.78 However, retinoblastomas may develop in many children who do not have a family history of eye cancer. Local therapy can be curative for small lesions, thus early diagnosis is important. Ultrasound of the eye can be useful for early diagnosis. In fetuses at risk, based on a family history and/or confirmed genetic mutations, there are anecdotal reports of focused evaluation of the eye with very thin MRI slices being used to identify early lesions. Whether early delivery of such fetuses to allow for early treatment should even be considered is debatable. By the time the lesions are visible on prenatal imaging, the benefits of early diagnosis may already be lost.
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5. Conclusions Access to prenatal care and advances in prenatal imaging have allowed the identification of lesions and tumors within the fetus. The differential diagnoses of these lesions is based upon the anatomic location and imaging characteristics on imaging. Adjunctive genetic studies may further refine the list of differential diagnoses. Most of these lesions will not have untoward consequences in fetal life and may be amenable to treatment postnatally. In selected rare cases, prenatal intervention may be life-saving and/ or reduce perinatal morbidity.
Practice points Fetal ultrasound and MRI are complementary in defining tissue characteristics of prenatal tumors. Multidisciplinary counseling is beneficial. An understanding of the perinatal natural history of the lesion will guide timing, location and mode of delivery. Fetal intervention is indicated only in select, rare cases.
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