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Disappearing fetal lung lesions
Disappearing Fetal Lung Lesions By Thomas E. MacGillivray, Michael R. Harrison, Ruth B. Goldstein, and N. Scott Adzick San Francisco, California 9 Cystic adenomatoid malformations and sequestrations of the lung are uncommon but potentially devastating problems of the fetus and neonate. We have followed over 50 cases of fetal lung masses from the time of prenatal diagnosis. Serial prenatal ultrasonography demonstrated that 9 large pulmonary lesions dramatically decreased in size or disappeared completely. We conclude that the natural history of prenatally diagnosed fetal lung masses is highly variable. A huge mass associated with fetal hydrops has a dismal outcome. If hydrops is not present, then the initial impression concerning prognosis may not accurately predict outcome, because there may be marked improvement during fetal life. Copyright 9 1993 by W.B. Saunders Company INDEX WORDS: Cystic adenomatoid malformation; pulmonary sequestration; prenatal diagnosis; fetal surgery.
H E R E HAS been an explosion of interest in
T prenatal diagnosis over the past decade sparked by improvements in ultrasonography. Prenatal diagnosis has helped define the natural history, pathophysiology, and optimal management of many fetal anatomic anomalies including fetal lung masses. 1 We have learned that the overall prognosis for a fetus with a thoracic mass depends on the size of the mass and the secondary physiologic derangement: a large mass can cause mediastinal shift, pulmonary hypoplasia, polyhydramnios, and cardiovascular compromise leading to fetal hydrops and death. However, in following over 50 cases of cystic adenomatoid malformation (CCAM) or pulmonary sequestration from the time of antenatal diagnosis, it is now apparent that some large fetal lung lesions can actually decrease in size and even disappear before birth. We present nine cases of prenatally diagnosed large pulmonary lesions (3 CCAMs and 6 sequestrations) associated with contralateral mediastinal shift that dramatically decreased in size over the course of pregnancy. CASE REPORTS Case 1 A 22-year-old woman (G1, P0) underwent a routine fetal ultrasound at 25 weeks gestation, which demonstrated a large right-sided intrathoracic mass (Fig 1A). The mass was echogenic and contained a few discernible small cysts consistent with a microcystic CCAM. 2 The lesion filled the entire fetal right hemithorax and shifted the heart and mediastinum to the left. At 30 weeks, although the size of the mass had not changed, polyhydramnios developed but hydrops was not present. The size of the mass was unchanged. At 33 weeks gestation, the mass appeared smaller and
Journalof Pediatric Surgery, Vo128,No 10 (October),1993:pp 1321-1325
the polyhydramnios resolved. The final ultrasound prior to birth performed at 36 weeks gestation showed that the mediastinum had returned to the midline and the mass was imperceptible (Fig 1B). After term delivery, the baby was asymptomatic and a chest x-ray showed a heterogeneous consolidation in the right lung base with multiple tubular and linear lucencies. A thoracic computed tomography (CT) scan showed a multicystic lesion in the right middle lobe with compression of the right lower lobe. The baby underwent a right thoracotomy with resection of the middle lobe. Gross and histological examination of the specimen confirmed the diagnosis of a type II CCAM. The baby continues to be well at 3 years of age. Comment. Prenatally diagnosed CCAMs have been classified based on gross anatomy and ultrasound findings.2 Macrocystic lesions contain single or multiple cysts of at least 5 mm diameter or larger, appear cystic on prenatal ultrasound, are not usually associated with hydrops, and have a more favorable prognosis. Microcystic lesions are more solid, appear echogenic on prenatal ultrasound, and are more commonly associated with pulmonary hypoplasia, fetal hydrops, and death. The overall prognosis depends primarily on the size of the CCAM rather than on the lesion type. Several other authors have previously described the partial involution of large echogenic fetal pulmonary lesions as determined by serial ultrasound examinations. 3-s
Case 2 A 21-year-old woman (G1, P0) underwent a routine sonogram at 22 weeks gestation that showed a male fetus with a large left-sided echogenic intrathoracic mass (Fig 2A). A prominent systemic artery arising from the aorta supplying the mass was visualized using color flow Doppler techniques, thereby suggesting the diagnosis of a pulmonary sequestration (Fig 2B). The heart and mediastinum were shifted to the right. By 27 weeks, polyhydramnios had developed without evidence of hydrops. Weekly sonographic examinations demonstrated a gradual decrease in the size of the mass. By 34 weeks, the amniotic fluid volume was normal, the mass was less conspicuous, and there was no longer any mediastinal shift. The sequestration was no longer visible by ultrasonography at 37 weeks (Fig 2C). The baby was clinically normal after term delivery and chest roentgenogram was also completely normal. A thoracic CT scan showed a diminutive soft tissue density in the left lower lung field above the diaphragm (Fig 2D). The baby continues to thrive at 6 months of age and surgery has not been performed.
From the Fetal Treatment Center, Division of Pediatric Surgery, and Department of Radiology, University of California, San Francisco, CA. Presented at the 1992Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, California, October 9-11, 1992. Supported in part by the Claude E. Welch Research Fellowship, Massachusetts General Hospital, Boston, MA. Address reprint requests to N. Scott Adzick, MD, Department of Surgery, 1601 HSW,, University of California, San Francisco, 3rd and Parnassus Ave, San Francisco, CA 94143-0570. Copyright 9 1993 by W.B. Saunders Company 0022-3468/93/2810-0020503.00/0
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Fig 1. (A) Prenatal ultrasound at 25 weeks gestation demonstrating a large, echogenic mass (*) filling the entire right chest and shifting of the heart (H) and mediastinum to the left. The fetal spine (S) marks the posterior midline. (B) By 36 weeks gestation, the heart (H) and mediastinum are midline and the mass is imperceptible. The fetal lungs (L) are normal in appearance.
Comment. T h e prenatal ultrasonographic appearance of a sequestration has been described as a well-defined, echo-dense, homogeneous mass in the lower chest or even in the abdomen. 6,7 Classified as bronchopulmonary foregut malformations, 8 sequestra-
tions are most commonly contiguous with the lower lobes, usually on the left side. 9 Pulmonary sequestrations are masses of nonfunctioning lung tissue supplied by an anomalous systemic artery. 1~ To our knowledge, this is the first reported case where an anomalous
Fig 2. (A) Prenatal ultrasound at 22 weeks gestation demonstrating a large, echogenic mass (*) in the left chest shifting the heart (H) and mediastinum to the right. (B) By Doppler studies, a systemic artery (curved arrow) from the descending aorta {Ao) is seen supplying the mass (~) consistent with the diagnosis of pulmonary sequestration. (C) By 37 weeks, the heart (H) is midline with normal appearing lungs (L). The mass is no longer visible by ultrasound. (D) Postnatal CT scan shows a small mass (*) in the left posterior chest.
DISAPPEARING FETAL LUNG LESIONS
systemic artery to a fetal lung lesion has been identified by prenatal Doppler techniques, which should be a pathognomonic sign of a pulmonary sequestration.
Other Cases Seven other cases of prenatally diagnosed intrathoracic lesions (2 CCAMs and 5 pulmonary sequestrations) also decreased in size over the course of pregnancy. CCAMs. One case of a right-sided CCAM presented as a large echogenic mass with contralateral mediastinal shift and fetal ascites at 26 weeks that completely resolved by 38 weeks. This baby was normal at birth without respiratory distress. Shortly after birth, a chest roentgenogram showed an area of hyperlucency in the right lower lobe. At 3 weeks of age, the baby underwent thoracotomy and right lower lobectomy for a type II CCAM. The other fetal CCAM was diagnosed at 21 weeks gestation and appeared as a large right-sided mass that produced eversion of the hemidiaphragm as well as contralateral mediastinal shift. By the time of delivery, near-complete regression of the mass had occurred. Postnatal CT scan showed a small area of cystic changes in the right lower lung. The child subsequently developed pneumonia in the abnormal area necessitating resection of the lesion. Sequestrations. Of the remaining five cases, all had large echogenic pulmonary lesions (3 left-sided and 2 right-sided) with contralateral mediastinal shift on the initial ultrasonographic examination. The final sonographic survey prior to birth could not demonstrate a mass in four cases and in the fifth case, the mass was barely perceptible. Only one baby had an abnormal chest x-ray and that child underwent resection of a left-sided extralobar sequestration. A systemic artery from the aorta to the sequestration was present. The other four children were normal at birth by both physical examination and chest x-ray. The diagnosis of sequestration was confirmed in one child by magnetic resonance imaging (MRI). Thoracic CT scans in the other three babies showed small opacities in the lower lung fields corresponding to the areas of the fetal lesions. They were presumed to be pulmonary sequestrations. All of the children have been followed closely since birth (range, 8 months to 3 years) and all are doing well. None have required surgery.
DISCUSSION
Prenatal detection and serial sonographic study of fetuses with lung masses have defined the natural history of these lesions, determined the pathophysiologic features that affect the outcome, and permitted formulation of management based on prognosis. Although a large pulmonary lesion diagnosed in utero might appear to be an ominous finding, the natural history of prenatally diagnosed pulmonary lesions is variable. Some fetuses will develop nonimmune hydrops fetalis whereas others, like the nine babies in our series, will have lesions that shrink. The exact mechanism by which these lesions shrink is unclear. The masses that shrank in our series and in the other reported cases were all echodense lesions. The echogenic appearance on ultrasonography is due to the large number of tissue/fluid interfaces. As the lung lesions decreased in size, they also became less eehogenic implying that they were losing fluid/tissue interfaces. CCAMs and sequestrations usually do not
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communicate directly with the tracheobronchial tree, although abnormal channels to the airway and the gastrointestinal tract have been reported. 9 Perhaps the lesions shrink due to decompression of fetal lung fluid through these abnormal channels. Another possible explanation is that the pulmonary lesions outgrow their vascular supply and involute. 11 It is unlikely that the lesions actually stayed the same size but appeared to shrink relative to the growing fetus, since some of the lesions disappeared completely by prenatal ultrasonography. Postnatally, a CCAM usually presents with neonatal respiratory distress or childhood infection. 12 The broad and dynamic spectrum of clinical severity with fetal CCAM is supported by this report since some initially large lesions can partially involute in utero. Conversely, huge CCAM lesions result in fetal cardiac compression, hydrops, and fetal death. 2 In these severely affected fetuses, fetal surgical resection of the lung mass is reasonably safe, reverses hydrops, and allows sufficient lung growth to permit survivai.13,14
Large fetal pulmonary sequestrations can also cause fetal hydrops, either from mass effect or from arteriovenous shunting of systemic blood through the sequestered lung leading to high output cardiac failure. 15 Detection by color flow Doppler of a systemic arterial blood supply from the aorta to the mass should be diagnostic of fetal pulmonary sequestration. The ability to differentiate intralobar and extralobar sequestration before birth is limited unless an extralobar sequestration is highlighted by a pleural effusion or located in the abdomen. There are no specific diagnostic hallmarks for the prenatal diagnosis of an intralobar sequestration. After birth, the most common clinical presentation of a sequestration is recurrent localized infection. Pulmonary sequestrations have also presented as congestive heart failure, hemothorax or as an asymptomatic pulmonary mass. 15,16 Despite the fact that sequestrations are considered by many to be uncommon, 1~these lesions appear as incidental findings in 1.1% to 1.8% of all patients undergoing pulmonary resection. 9 This would suggest that most sequestrations are asymptomatic and go unnoticed. Standard practice dictates that the mere presence of a CCAM or a sequestration is an indication for resection. This implies that the diagnosis must have been made either by symptoms or radiographic findings. The three babies with CCAMs in this series had abnormal chest x-rays after birth and they all had their lesions resected. Because pulmonary malignancy arising in a CCAM has been reported, resection is indicated even if a CCAM is asymptomatic,t7,18
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MACGILLIVRAY ET AL
Only one of the children with presumed sequestration had an abnormal chest x-ray at birth and she had an extralobar sequestration resected. The other five children had normal chest x-rays and only very subtle changes on thoracic CT scan or MRI. None of these five children have had any symptoms and none have required surgery. If not for the findings on prenatal ultrasound, these lesions would have most likely gone completely undiscovered. Therefore, we feel that these children should be observed closely and managed without resection unless they become symptomatic. 19 When a pulmonary lesion is diagnosed in utero, the prognosis can be quite variable. If the fetus develops hydrops before 32 weeks gestation, the prognosis is grim. Fetal surgery has been used successfully to treat these jeopardized fetuses. 14 For those fetuses greater than 32 weeks with hydrops, early delivery and ex
utero resection should be considered. In the absence of hydrops, even large pulmonary lesions may shrink in size and possibly even disappear. These fetuses should be examined frequently by serial ultrasound to detect the development of hydrops. At birth, if babies with pulmonary masses are symptomatic or have lesions large enough to be seen on chest x-ray, resection of the lesion should be considered. In the absence of symptoms and radiological abnormalities, expectant management is reasonable. As we continue to learn more about the fetus, we have begun to appreciate that "things are not always as they seem." The natural history of fetal pulmonary lesions is dynamic and variable. Initial impressions concerning the prognosis of large pulmonary lesions should be tempered with the understanding that they can shrink in size and even disappear.
REFERENCES
1. Harrison MR, Adzick NS: The fetus as a patient: Surgical considerations. Ann Surg 213:279-291,1991 2. Adzick NS, Harrison MR, Glick PL, et al: Fetal cystic adenomatoid malformation: Prenatal diagnosis and natural history. J Pediatr Surg 20:483-488,1985 3. KullerJA, Laifer SA, Tagge EP, et al: Diminution in size of a fetal intrathoracic mass: Caution against aggressive in utero management. Am J Perinatol 9:223-224, 1992 4. Fine C, Adzick NS, Doubilet PM: Decreasing size of a congenital cysticadenomatoid malformation in utero. J Ultrasound Med 7:405-408,1988 5. Saltzman DH, Adzick NS, Benacerraf BR: Fetal cystic adenomatoid malformation of the lung: Apparent improvement in utero. Obstet Gyneco171:1000-1002,1988 6. Maulik D, Robinson L, Daily D, et al: Prenatal sonographic depiction of intralobar pulmonary sequestration. J Ultrasound Med 6:703-706,1987 7. Weinbaum PJ, Bors-Koefoed R, Green K, et al: Antenatal sonographic findings in a case of intra-abdominal pulmonary sequestration. Obstet Gyneco173:860-861,1989 8. FowlerCL, PokornyWJ, WagnerML: Reviewof bronchopulmonary foregut malformations. J Pediatr Surg 23:793-797,1988 9. Carter R: Pulmonary sequestration (collective review). Ann Thorac Surg 7:68-88, 1969 10. Sieber WK: Lung cysts, sequestration, and bronchopulmonary dysplasia, in Welch KJ, Randolph JG, Ravitch MM, et al (eds): Pediatric Surgery.Chicago,IL, Year Book, 1986, pp 645-654
11. Gerle RD, Jaretzki AI, Ashley CA, et al: Congenital bronchopulmonaryforegut malformation. N Engl J Med 278:14131419, 1968 12. Miller RK, Sieber WK, Yunis EJ: Congenital adenomatoid malformation of the lung. Pathol Ann 15:387-407,1980 13. Harrison MR, AdzickNS, Jennings RW: Antenatal intervention for congenital cystic adenomatoid malformation. Lancet 336:965-967, 1990 14. AdzickNS, Harrison MR, Flake AW, et al: Fetal surgeryfor cystic adenomatoid malformation of the lung. J Pediatr Surg 28:806-812, 1993 15. Levine MM, Nudel DB, Gootman N, et al: Pulmonary sequestration causing congestive heart failure in infancy:A report of two cases and a review of the literature. Ann Thorac Surg
34:581-585, 1982 16. Laurin S, Aronson S, Schuller H, et al: Spontaneous hemothorax from bronchopulmonarysequestration. Pediatr Radiol 10: 54-56, 1980 17. SheffieldEA, Addis BJ, Corrin B, et al: Epithelial hyperplasia and malignant change in congenital lung cysts. J Clin Pathol 40:612-614, 1987 18. Ueda K, Gruppo R, Unger F, et al: Rhabdomyosarcomaof lung arising in congenital cystic adenomatoid malformation. Cancer 40:383-388,1977 19. Shamji FM, Sachs HJ, Perkins DG: Cystic disease of the lungs. Surg Clin North Am 68:581-620,1988
Discussion A. Hailer (Baltimore, MD): In your manuscript you emphasize the original observation that the cystic congenital adenomatoid malformations appears to be histologically different in that there are microcystic forms and macrocystic forms. From your laboratory you have suggested that the microcystic forms were the ones that were most likely to end in fetal death or have a high mortality at birth. But now what I believe
you are saying is that it is not the histological finding, but rather that more commonly the microcystic lesions are associated with hydrops and it is the hydrops which is responsible for the mortality. Recently another resident working in your laboratory, Dr Rice, before the Residents' Conference gave a fascinating abstract of a small number of animals in which he had used a tissue expander to shift the
DISAPPEARING FETAL LUNG LESIONS
mediastinum in fetuses and produce, just by shifting the mediastinum, hydrops. In one of those four animals he deflated that tissue expander in the chest and the hydrops disappeared. Now, if that can be repeated, this will be for the first time an explanation of the hydrops associated with some of these space-occupying lesions; namely, an increase in central venous pressure as a result of interfering with venous return to the right side of the heart and thus a form of acute or chronic corpulmonale in the fetus. This gives us a very nice explanation for the observation that Dr Harrison and his group have been talking about over the last several years. The other comment that you did not have time to allude to is an unpublished manuscript in which your group has operated upon six cases in utero of cystic adenomatoid malformation of the lung with two deaths in that group. All six of those patients required lobectomy because the mass was large and all had hydrops. So if I understand correctly, the clear indication in those rare instances in which fetal surgery is necessary it is the hydrops, not the histologic nature of the lesion itself. What impresses me is that your group has now brought leavening to this area of controversy, because now we see the spectrum. Now there are lesions you're reporting which do not go on to death of the fetus and do not require intrauterine operative procedures; and, indeed, many of them do not require operation after birth because they have disappeared. So I believe we're at the point that if this lesion is associated with hydrops there is such a high likelihood of mortality that if you are prepared to carry out intrauterine surgery these are the patients most likely to benefit from it. The others should be watched very, very carefully, and many of them will, if they don't disappear, be good candidates, as Dr Wesley and his associates showed us, for early intervention. I do have a couple of questions for you: If the key to this is hydrops with the shift of the heart, why don't we see more hydrops associated with the fetuses that have congenital diaphragmatic hernia where there is such a marked shift of the mediastinum? To my knowledge hydrops is a very rarely associated component of that lesion? Second, do you think the polyhydramnios that sometimes is associated with these lesions is due to a shift of the mediastinum and compression of the esophagus and, therefore, there is an accumulation of amniotic fluid? Or is that too simple an explanation? And, finally, how early do you think this diagnosis can be made? It is obviously important to all of us, if we're going to follow these and be involved with our prenatal diagnostic group, to know when we should be looking for this and then to
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carefully monitor the further evolution of these lesions. T. MacGillivray (response): We believe that these fetal lung lesions cause fetal hydrops because of the physiologic derangement they produce rather than the histologic type of the lesion. In our laboratory, Dr Henry Rice has developed a chronic fetal lamb model simulating a growing intrathoracic mass which can be watched by prenatal ultrasound. With gradual inflation of a tissue expander, impaired venous return and direct cardiac compression occurs resulting in hydrops. With deflation of the expander to simulate fetal surgical resection of the lung lesion, the hydrops resolves. It is unclear why we do not see hydrops more frequently in fetuses with diaphragmatic hernias. Perhaps, the defect in the diaphragm prevents detrimental elevation of intrathoracic pressure by allowing equilibration through the abdomen. Like you, we also believe that fetuses with diaphragmatic hernias develop polyhydramnios because of esophageal obstruction and consequent interference with fetal swallowing of amniotic fluid. As prenatal ultrasound continues to improve, we are able to identify fetal anomalies at earlier gestational ages. We have diagnosed fetal lung lesions as early as 17 weeks gestation. H. Cheu (San Antonio, TX): We've had an opportunity to treat two patients who were diagnosed in utero, transferred to our center, and at birth had minimally abnormal lungs. In both patients, the chest x-ray was nearly normal. If one didn't know, based on the prenatal ultrasound that there was something abnormal, the findings may well have been dismissed as insignificant. On CT and MRI the lesions were obvious. We weren't sure whether we should take these out or observe the patients closely. Dr Wesley's poster recommends elective resection even in asymptomatic infants. Your group has chosen to observe five patients. It will be important to know the natural history of these subtle and previously undetected lesions. T. MacGillivray (response): Before you can treat something, you obviously need to make the diagnosis. Pulmonary sequestrations are found incidentally in 1.1% to 1.8% of all patients undergoing thoracotomy which otherwise would have gone unnoticed (Carter R: Ann Thorac Surg 7:66-68, 1969). In the absence of symptoms or an abnormal chest x-ray, there does not appear to be anything to treat. In our series of babies with disappearing fetal lung lesions, none of the babies that we have followed without surgery have had any trouble.
H E R E HAS been an explosion of interest in
T prenatal diagnosis over the past decade sparked by improvements in ultrasonography. Prenatal diagnosis has helped define the natural history, pathophysiology, and optimal management of many fetal anatomic anomalies including fetal lung masses. 1 We have learned that the overall prognosis for a fetus with a thoracic mass depends on the size of the mass and the secondary physiologic derangement: a large mass can cause mediastinal shift, pulmonary hypoplasia, polyhydramnios, and cardiovascular compromise leading to fetal hydrops and death. However, in following over 50 cases of cystic adenomatoid malformation (CCAM) or pulmonary sequestration from the time of antenatal diagnosis, it is now apparent that some large fetal lung lesions can actually decrease in size and even disappear before birth. We present nine cases of prenatally diagnosed large pulmonary lesions (3 CCAMs and 6 sequestrations) associated with contralateral mediastinal shift that dramatically decreased in size over the course of pregnancy. CASE REPORTS Case 1 A 22-year-old woman (G1, P0) underwent a routine fetal ultrasound at 25 weeks gestation, which demonstrated a large right-sided intrathoracic mass (Fig 1A). The mass was echogenic and contained a few discernible small cysts consistent with a microcystic CCAM. 2 The lesion filled the entire fetal right hemithorax and shifted the heart and mediastinum to the left. At 30 weeks, although the size of the mass had not changed, polyhydramnios developed but hydrops was not present. The size of the mass was unchanged. At 33 weeks gestation, the mass appeared smaller and
Journalof Pediatric Surgery, Vo128,No 10 (October),1993:pp 1321-1325
the polyhydramnios resolved. The final ultrasound prior to birth performed at 36 weeks gestation showed that the mediastinum had returned to the midline and the mass was imperceptible (Fig 1B). After term delivery, the baby was asymptomatic and a chest x-ray showed a heterogeneous consolidation in the right lung base with multiple tubular and linear lucencies. A thoracic computed tomography (CT) scan showed a multicystic lesion in the right middle lobe with compression of the right lower lobe. The baby underwent a right thoracotomy with resection of the middle lobe. Gross and histological examination of the specimen confirmed the diagnosis of a type II CCAM. The baby continues to be well at 3 years of age. Comment. Prenatally diagnosed CCAMs have been classified based on gross anatomy and ultrasound findings.2 Macrocystic lesions contain single or multiple cysts of at least 5 mm diameter or larger, appear cystic on prenatal ultrasound, are not usually associated with hydrops, and have a more favorable prognosis. Microcystic lesions are more solid, appear echogenic on prenatal ultrasound, and are more commonly associated with pulmonary hypoplasia, fetal hydrops, and death. The overall prognosis depends primarily on the size of the CCAM rather than on the lesion type. Several other authors have previously described the partial involution of large echogenic fetal pulmonary lesions as determined by serial ultrasound examinations. 3-s
Case 2 A 21-year-old woman (G1, P0) underwent a routine sonogram at 22 weeks gestation that showed a male fetus with a large left-sided echogenic intrathoracic mass (Fig 2A). A prominent systemic artery arising from the aorta supplying the mass was visualized using color flow Doppler techniques, thereby suggesting the diagnosis of a pulmonary sequestration (Fig 2B). The heart and mediastinum were shifted to the right. By 27 weeks, polyhydramnios had developed without evidence of hydrops. Weekly sonographic examinations demonstrated a gradual decrease in the size of the mass. By 34 weeks, the amniotic fluid volume was normal, the mass was less conspicuous, and there was no longer any mediastinal shift. The sequestration was no longer visible by ultrasonography at 37 weeks (Fig 2C). The baby was clinically normal after term delivery and chest roentgenogram was also completely normal. A thoracic CT scan showed a diminutive soft tissue density in the left lower lung field above the diaphragm (Fig 2D). The baby continues to thrive at 6 months of age and surgery has not been performed.
From the Fetal Treatment Center, Division of Pediatric Surgery, and Department of Radiology, University of California, San Francisco, CA. Presented at the 1992Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, California, October 9-11, 1992. Supported in part by the Claude E. Welch Research Fellowship, Massachusetts General Hospital, Boston, MA. Address reprint requests to N. Scott Adzick, MD, Department of Surgery, 1601 HSW,, University of California, San Francisco, 3rd and Parnassus Ave, San Francisco, CA 94143-0570. Copyright 9 1993 by W.B. Saunders Company 0022-3468/93/2810-0020503.00/0
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Fig 1. (A) Prenatal ultrasound at 25 weeks gestation demonstrating a large, echogenic mass (*) filling the entire right chest and shifting of the heart (H) and mediastinum to the left. The fetal spine (S) marks the posterior midline. (B) By 36 weeks gestation, the heart (H) and mediastinum are midline and the mass is imperceptible. The fetal lungs (L) are normal in appearance.
Comment. T h e prenatal ultrasonographic appearance of a sequestration has been described as a well-defined, echo-dense, homogeneous mass in the lower chest or even in the abdomen. 6,7 Classified as bronchopulmonary foregut malformations, 8 sequestra-
tions are most commonly contiguous with the lower lobes, usually on the left side. 9 Pulmonary sequestrations are masses of nonfunctioning lung tissue supplied by an anomalous systemic artery. 1~ To our knowledge, this is the first reported case where an anomalous
Fig 2. (A) Prenatal ultrasound at 22 weeks gestation demonstrating a large, echogenic mass (*) in the left chest shifting the heart (H) and mediastinum to the right. (B) By Doppler studies, a systemic artery (curved arrow) from the descending aorta {Ao) is seen supplying the mass (~) consistent with the diagnosis of pulmonary sequestration. (C) By 37 weeks, the heart (H) is midline with normal appearing lungs (L). The mass is no longer visible by ultrasound. (D) Postnatal CT scan shows a small mass (*) in the left posterior chest.
DISAPPEARING FETAL LUNG LESIONS
systemic artery to a fetal lung lesion has been identified by prenatal Doppler techniques, which should be a pathognomonic sign of a pulmonary sequestration.
Other Cases Seven other cases of prenatally diagnosed intrathoracic lesions (2 CCAMs and 5 pulmonary sequestrations) also decreased in size over the course of pregnancy. CCAMs. One case of a right-sided CCAM presented as a large echogenic mass with contralateral mediastinal shift and fetal ascites at 26 weeks that completely resolved by 38 weeks. This baby was normal at birth without respiratory distress. Shortly after birth, a chest roentgenogram showed an area of hyperlucency in the right lower lobe. At 3 weeks of age, the baby underwent thoracotomy and right lower lobectomy for a type II CCAM. The other fetal CCAM was diagnosed at 21 weeks gestation and appeared as a large right-sided mass that produced eversion of the hemidiaphragm as well as contralateral mediastinal shift. By the time of delivery, near-complete regression of the mass had occurred. Postnatal CT scan showed a small area of cystic changes in the right lower lung. The child subsequently developed pneumonia in the abnormal area necessitating resection of the lesion. Sequestrations. Of the remaining five cases, all had large echogenic pulmonary lesions (3 left-sided and 2 right-sided) with contralateral mediastinal shift on the initial ultrasonographic examination. The final sonographic survey prior to birth could not demonstrate a mass in four cases and in the fifth case, the mass was barely perceptible. Only one baby had an abnormal chest x-ray and that child underwent resection of a left-sided extralobar sequestration. A systemic artery from the aorta to the sequestration was present. The other four children were normal at birth by both physical examination and chest x-ray. The diagnosis of sequestration was confirmed in one child by magnetic resonance imaging (MRI). Thoracic CT scans in the other three babies showed small opacities in the lower lung fields corresponding to the areas of the fetal lesions. They were presumed to be pulmonary sequestrations. All of the children have been followed closely since birth (range, 8 months to 3 years) and all are doing well. None have required surgery.
DISCUSSION
Prenatal detection and serial sonographic study of fetuses with lung masses have defined the natural history of these lesions, determined the pathophysiologic features that affect the outcome, and permitted formulation of management based on prognosis. Although a large pulmonary lesion diagnosed in utero might appear to be an ominous finding, the natural history of prenatally diagnosed pulmonary lesions is variable. Some fetuses will develop nonimmune hydrops fetalis whereas others, like the nine babies in our series, will have lesions that shrink. The exact mechanism by which these lesions shrink is unclear. The masses that shrank in our series and in the other reported cases were all echodense lesions. The echogenic appearance on ultrasonography is due to the large number of tissue/fluid interfaces. As the lung lesions decreased in size, they also became less eehogenic implying that they were losing fluid/tissue interfaces. CCAMs and sequestrations usually do not
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communicate directly with the tracheobronchial tree, although abnormal channels to the airway and the gastrointestinal tract have been reported. 9 Perhaps the lesions shrink due to decompression of fetal lung fluid through these abnormal channels. Another possible explanation is that the pulmonary lesions outgrow their vascular supply and involute. 11 It is unlikely that the lesions actually stayed the same size but appeared to shrink relative to the growing fetus, since some of the lesions disappeared completely by prenatal ultrasonography. Postnatally, a CCAM usually presents with neonatal respiratory distress or childhood infection. 12 The broad and dynamic spectrum of clinical severity with fetal CCAM is supported by this report since some initially large lesions can partially involute in utero. Conversely, huge CCAM lesions result in fetal cardiac compression, hydrops, and fetal death. 2 In these severely affected fetuses, fetal surgical resection of the lung mass is reasonably safe, reverses hydrops, and allows sufficient lung growth to permit survivai.13,14
Large fetal pulmonary sequestrations can also cause fetal hydrops, either from mass effect or from arteriovenous shunting of systemic blood through the sequestered lung leading to high output cardiac failure. 15 Detection by color flow Doppler of a systemic arterial blood supply from the aorta to the mass should be diagnostic of fetal pulmonary sequestration. The ability to differentiate intralobar and extralobar sequestration before birth is limited unless an extralobar sequestration is highlighted by a pleural effusion or located in the abdomen. There are no specific diagnostic hallmarks for the prenatal diagnosis of an intralobar sequestration. After birth, the most common clinical presentation of a sequestration is recurrent localized infection. Pulmonary sequestrations have also presented as congestive heart failure, hemothorax or as an asymptomatic pulmonary mass. 15,16 Despite the fact that sequestrations are considered by many to be uncommon, 1~these lesions appear as incidental findings in 1.1% to 1.8% of all patients undergoing pulmonary resection. 9 This would suggest that most sequestrations are asymptomatic and go unnoticed. Standard practice dictates that the mere presence of a CCAM or a sequestration is an indication for resection. This implies that the diagnosis must have been made either by symptoms or radiographic findings. The three babies with CCAMs in this series had abnormal chest x-rays after birth and they all had their lesions resected. Because pulmonary malignancy arising in a CCAM has been reported, resection is indicated even if a CCAM is asymptomatic,t7,18
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MACGILLIVRAY ET AL
Only one of the children with presumed sequestration had an abnormal chest x-ray at birth and she had an extralobar sequestration resected. The other five children had normal chest x-rays and only very subtle changes on thoracic CT scan or MRI. None of these five children have had any symptoms and none have required surgery. If not for the findings on prenatal ultrasound, these lesions would have most likely gone completely undiscovered. Therefore, we feel that these children should be observed closely and managed without resection unless they become symptomatic. 19 When a pulmonary lesion is diagnosed in utero, the prognosis can be quite variable. If the fetus develops hydrops before 32 weeks gestation, the prognosis is grim. Fetal surgery has been used successfully to treat these jeopardized fetuses. 14 For those fetuses greater than 32 weeks with hydrops, early delivery and ex
utero resection should be considered. In the absence of hydrops, even large pulmonary lesions may shrink in size and possibly even disappear. These fetuses should be examined frequently by serial ultrasound to detect the development of hydrops. At birth, if babies with pulmonary masses are symptomatic or have lesions large enough to be seen on chest x-ray, resection of the lesion should be considered. In the absence of symptoms and radiological abnormalities, expectant management is reasonable. As we continue to learn more about the fetus, we have begun to appreciate that "things are not always as they seem." The natural history of fetal pulmonary lesions is dynamic and variable. Initial impressions concerning the prognosis of large pulmonary lesions should be tempered with the understanding that they can shrink in size and even disappear.
REFERENCES
1. Harrison MR, Adzick NS: The fetus as a patient: Surgical considerations. Ann Surg 213:279-291,1991 2. Adzick NS, Harrison MR, Glick PL, et al: Fetal cystic adenomatoid malformation: Prenatal diagnosis and natural history. J Pediatr Surg 20:483-488,1985 3. KullerJA, Laifer SA, Tagge EP, et al: Diminution in size of a fetal intrathoracic mass: Caution against aggressive in utero management. Am J Perinatol 9:223-224, 1992 4. Fine C, Adzick NS, Doubilet PM: Decreasing size of a congenital cysticadenomatoid malformation in utero. J Ultrasound Med 7:405-408,1988 5. Saltzman DH, Adzick NS, Benacerraf BR: Fetal cystic adenomatoid malformation of the lung: Apparent improvement in utero. Obstet Gyneco171:1000-1002,1988 6. Maulik D, Robinson L, Daily D, et al: Prenatal sonographic depiction of intralobar pulmonary sequestration. J Ultrasound Med 6:703-706,1987 7. Weinbaum PJ, Bors-Koefoed R, Green K, et al: Antenatal sonographic findings in a case of intra-abdominal pulmonary sequestration. Obstet Gyneco173:860-861,1989 8. FowlerCL, PokornyWJ, WagnerML: Reviewof bronchopulmonary foregut malformations. J Pediatr Surg 23:793-797,1988 9. Carter R: Pulmonary sequestration (collective review). Ann Thorac Surg 7:68-88, 1969 10. Sieber WK: Lung cysts, sequestration, and bronchopulmonary dysplasia, in Welch KJ, Randolph JG, Ravitch MM, et al (eds): Pediatric Surgery.Chicago,IL, Year Book, 1986, pp 645-654
11. Gerle RD, Jaretzki AI, Ashley CA, et al: Congenital bronchopulmonaryforegut malformation. N Engl J Med 278:14131419, 1968 12. Miller RK, Sieber WK, Yunis EJ: Congenital adenomatoid malformation of the lung. Pathol Ann 15:387-407,1980 13. Harrison MR, AdzickNS, Jennings RW: Antenatal intervention for congenital cystic adenomatoid malformation. Lancet 336:965-967, 1990 14. AdzickNS, Harrison MR, Flake AW, et al: Fetal surgeryfor cystic adenomatoid malformation of the lung. J Pediatr Surg 28:806-812, 1993 15. Levine MM, Nudel DB, Gootman N, et al: Pulmonary sequestration causing congestive heart failure in infancy:A report of two cases and a review of the literature. Ann Thorac Surg
34:581-585, 1982 16. Laurin S, Aronson S, Schuller H, et al: Spontaneous hemothorax from bronchopulmonarysequestration. Pediatr Radiol 10: 54-56, 1980 17. SheffieldEA, Addis BJ, Corrin B, et al: Epithelial hyperplasia and malignant change in congenital lung cysts. J Clin Pathol 40:612-614, 1987 18. Ueda K, Gruppo R, Unger F, et al: Rhabdomyosarcomaof lung arising in congenital cystic adenomatoid malformation. Cancer 40:383-388,1977 19. Shamji FM, Sachs HJ, Perkins DG: Cystic disease of the lungs. Surg Clin North Am 68:581-620,1988
Discussion A. Hailer (Baltimore, MD): In your manuscript you emphasize the original observation that the cystic congenital adenomatoid malformations appears to be histologically different in that there are microcystic forms and macrocystic forms. From your laboratory you have suggested that the microcystic forms were the ones that were most likely to end in fetal death or have a high mortality at birth. But now what I believe
you are saying is that it is not the histological finding, but rather that more commonly the microcystic lesions are associated with hydrops and it is the hydrops which is responsible for the mortality. Recently another resident working in your laboratory, Dr Rice, before the Residents' Conference gave a fascinating abstract of a small number of animals in which he had used a tissue expander to shift the
DISAPPEARING FETAL LUNG LESIONS
mediastinum in fetuses and produce, just by shifting the mediastinum, hydrops. In one of those four animals he deflated that tissue expander in the chest and the hydrops disappeared. Now, if that can be repeated, this will be for the first time an explanation of the hydrops associated with some of these space-occupying lesions; namely, an increase in central venous pressure as a result of interfering with venous return to the right side of the heart and thus a form of acute or chronic corpulmonale in the fetus. This gives us a very nice explanation for the observation that Dr Harrison and his group have been talking about over the last several years. The other comment that you did not have time to allude to is an unpublished manuscript in which your group has operated upon six cases in utero of cystic adenomatoid malformation of the lung with two deaths in that group. All six of those patients required lobectomy because the mass was large and all had hydrops. So if I understand correctly, the clear indication in those rare instances in which fetal surgery is necessary it is the hydrops, not the histologic nature of the lesion itself. What impresses me is that your group has now brought leavening to this area of controversy, because now we see the spectrum. Now there are lesions you're reporting which do not go on to death of the fetus and do not require intrauterine operative procedures; and, indeed, many of them do not require operation after birth because they have disappeared. So I believe we're at the point that if this lesion is associated with hydrops there is such a high likelihood of mortality that if you are prepared to carry out intrauterine surgery these are the patients most likely to benefit from it. The others should be watched very, very carefully, and many of them will, if they don't disappear, be good candidates, as Dr Wesley and his associates showed us, for early intervention. I do have a couple of questions for you: If the key to this is hydrops with the shift of the heart, why don't we see more hydrops associated with the fetuses that have congenital diaphragmatic hernia where there is such a marked shift of the mediastinum? To my knowledge hydrops is a very rarely associated component of that lesion? Second, do you think the polyhydramnios that sometimes is associated with these lesions is due to a shift of the mediastinum and compression of the esophagus and, therefore, there is an accumulation of amniotic fluid? Or is that too simple an explanation? And, finally, how early do you think this diagnosis can be made? It is obviously important to all of us, if we're going to follow these and be involved with our prenatal diagnostic group, to know when we should be looking for this and then to
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carefully monitor the further evolution of these lesions. T. MacGillivray (response): We believe that these fetal lung lesions cause fetal hydrops because of the physiologic derangement they produce rather than the histologic type of the lesion. In our laboratory, Dr Henry Rice has developed a chronic fetal lamb model simulating a growing intrathoracic mass which can be watched by prenatal ultrasound. With gradual inflation of a tissue expander, impaired venous return and direct cardiac compression occurs resulting in hydrops. With deflation of the expander to simulate fetal surgical resection of the lung lesion, the hydrops resolves. It is unclear why we do not see hydrops more frequently in fetuses with diaphragmatic hernias. Perhaps, the defect in the diaphragm prevents detrimental elevation of intrathoracic pressure by allowing equilibration through the abdomen. Like you, we also believe that fetuses with diaphragmatic hernias develop polyhydramnios because of esophageal obstruction and consequent interference with fetal swallowing of amniotic fluid. As prenatal ultrasound continues to improve, we are able to identify fetal anomalies at earlier gestational ages. We have diagnosed fetal lung lesions as early as 17 weeks gestation. H. Cheu (San Antonio, TX): We've had an opportunity to treat two patients who were diagnosed in utero, transferred to our center, and at birth had minimally abnormal lungs. In both patients, the chest x-ray was nearly normal. If one didn't know, based on the prenatal ultrasound that there was something abnormal, the findings may well have been dismissed as insignificant. On CT and MRI the lesions were obvious. We weren't sure whether we should take these out or observe the patients closely. Dr Wesley's poster recommends elective resection even in asymptomatic infants. Your group has chosen to observe five patients. It will be important to know the natural history of these subtle and previously undetected lesions. T. MacGillivray (response): Before you can treat something, you obviously need to make the diagnosis. Pulmonary sequestrations are found incidentally in 1.1% to 1.8% of all patients undergoing thoracotomy which otherwise would have gone unnoticed (Carter R: Ann Thorac Surg 7:66-68, 1969). In the absence of symptoms or an abnormal chest x-ray, there does not appear to be anything to treat. In our series of babies with disappearing fetal lung lesions, none of the babies that we have followed without surgery have had any trouble.