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Long term respiratory outcomes of congenital thoracic malformations
Seminars in Fetal & Neonatal Medicine 17 (2012) 99e104
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Long term respiratory outcomes of congenital thoracic malformations Mark Davenport a, *, Ernst Eber b a b
Department of Paediatric Surgery, King’s College Hospital, London, UK Respiratory and Allergic Disease Division, Department of Paediatrics, Medical University of Graz, Graz, Austria
s u m m a r y Keywords: Bronchopulmonary sequestration Congenital cystic adenomatoid malformation Congenital lobar emphysema Lobectomy Congenital thoracic malformation Malignancy change
The advent of universal antenatal ultrasonography in many countries has revealed the full spectrum of congenital thoracic malformations (CTMs) and presented clinicians with a number of practical dilemmas to do with diagnosis and management. We present a review of the most common forms of CTMs, including congenital cystic adenomatoid malformation, bronchopulmonary sequestration, and lobar and segmental emphysema. Ó 2012 Published by Elsevier Ltd.
1. Introduction The term congenital thoracic malformation (CTM) is an umbrella phrase for developmental lesions present at birth derived from lung and its adnexal tissue, but which confers no actual histological meaning or implied derivation. Included under this umbrella are true pulmonary parenchymal lesions such as the various types of congenital cystic adenomatoid malformation (CCAM), extra- and intralobar bronchopulmonary sequestration and congenital lobar and segmental emphysemas together with less common entities such as foregut duplication and bronchogenic cysts. The characteristics of each will be outlined later. The aim of this review is to summarise our current understanding of such lesions with a focus on what may happen outside of infancy to those who have been treated to the usual therapy e surgical resection e and those where a more conservative approach has been taken.
worked out as an incidence of 4.44 per 10,000 fetuses and translated to an incidence of 3.52 per 10,000 live births. During that year the estimated incidence of CCAM was 0.7 per 10,000 live births, or about one-quarter of all CTMs. 3. Common origin of congenital thoracic malformations It is thought that lung parenchymal malformations although superficially heterogeneous in appearance, share a common embryological origin and have significant overlap. Although not an original concept, Langston re-proposed that disordered parenchymal development might be attributed to in-utero airway obstruction,2 with the level, timing and the completeness of the obstruction producing different patterns of lung malformation. There is histological evidence for peripheral bronchial atresia/ stenosis in many apparently separate entities,3 but the mode and timing of these events is still speculative.
2. Incidence
4. Congenital cystic adenomatoid malformation (CCAM)
The European Surveillance of Congenital Anomalies (EUROCAT) was established in 1979 with the aim of providing a network of population-based registers for the epidemiological surveillance of congenital anomalies. Data have been collected from 43 European registries in 20 European countries with an estimated capture of about 29% of Europe’s birth population.1 The EUROCAT database showed that in 2008, there were 222 fetuses with a CTM, which
The first clinical report by Ch’in and Tang of what was termed congenital adenomatoid malformation appeared in 1947.4 In 1975, Garrett et al.5 first reported the antenatal detection of a CCAM using greyscale ultrasound which heralded the current era in which >90% of lesions are detected in antenatal screening programmes. Although early reports in the obstetric literature6e8 were characterised by large lesions, a marked association with other abnormalities and a poor prognosis, we now realise that the majority are relatively small lesions, which are usually asymptomatic, at least in early postnatal life.9,10 CCAMs appear to be derived from the proliferation of peripheral bronchiolar tissue at the expense of alveolar tissues with a single
* Corresponding author. Address: Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel.: þ44 (0) 203 299 3350; fax: þ44 (0) 203 299 4021. E-mail address: [email protected] (M. Davenport). 1744-165X/$ e see front matter Ó 2012 Published by Elsevier Ltd. doi:10.1016/j.siny.2012.01.011
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lobe affected in >95% of cases with no particular preference for side,9e12 though there is a predilection for the basal lobes. Bilateral lesions are uncommon (<3%) and usually have a poor prognosis.7 The original Stocker classification13 was based on postnatal histology and originally divided CCAMs into three types (1, 2 and 3). Subsequently the rarer types 0 and 4 were also proposed, expanding the classification so that type 0 was an essentially tracheobronchial defect (also known as acinar dysplasia) and characterised by firm small lungs with a bronchial airway; and type 4 an entirely alveolar defect occurring at the periphery of the lungs.14 It is noteworthy that only types 1e3 are adenomatoid and only types 1, 2 and 4 are cystic and it is also noteworthy that Stocker himself proposed a new name for such lesions e congenital pulmonary airway malformation (CPAM) e although whether this will replace CCAM only time will tell. Type 4 CCAM is a more controversial entity as its features overlap with type 1 pleuropulmonary blastoma, the only distinguishing feature being a lack of blastema in type 4 CCAM.15 The current characteristics of the classification are summarized in Table 1.
4.1. Clinical features As befits the complexity and variation in pathology, the nature of clinical features also varies considerably. In fetal life, large spaceoccupying lesions (of whatever histology) may cause mediastinal shift, impairment of venous return and hydrops leading to fetal demise typically in the third trimester.6,7 A proportion (<20%) will cause early respiratory distress within the first month after birth requiring early surgical excision.8e10,16 The remainder are asymptomatic but are prone to develop infection (pneumonia, lung abscess, empyema, etc.) and occasionally cyst rupture leading to pneumothorax. A recent systematic literature review has suggested that the median age of symptom development in this group was about 10 months.17 The malignant potential of such lesions will be addressed in detail later.
Intralobar sequestration (ILS): often embedded in normal parenchyma and covered by visceral pleura in continuity with the normal lung. The venous drainage is usually into the pulmonary vein. Extralobar sequestration (ELS): invariably solid with its own separate pleural covering, separate from the normal lung. Most sequestrations are medio-basal in location (left > right) and about 10% are actually located below the diaphragm.20 ELS may be found in association with diaphragmatic hernias, but other anomalies are less common (e.g. chest wall anomalies, vertebral deformities, hindgut duplications and congenital heart disease). Very large sequestrations can act as space-occupying lesions and diminish respiratory reserve but most appear silent. A peculiar complication, not seen with CCAM, is high output cardiac failure associated with the sequestration’s redundant circulation and occasionally massive left-to-left shunt. Some of these will present during the antenatal period21 with hydrothorax and pleural effusion, requiring in-utero drainage. A novel approach to some obvious echogenic lesions (usually thought to be sequestrations) has been in-utero laser ablation.22 6. Hybrid lesions This term refers to the overlap between CCAM and sequestration.23 Several surgical series have shown that some lesions do not fit neatly into the above two categories and are usually labelled hybrids.9 Features might include: Anatomical ELS but with histological appearance more compatible with CCAM; ELS and CCAM occurring in the same patient; Obvious CCAM lesions in a lobe but with an accessory systemic blood supply.
7. Lobar and segmental emphysema 5. Bronchopulmonary sequestrations Bronchopulmonary sequestrations were first termed ‘accessory pulmonary lobes’ by Rokitansky in 1861, but later renamed ‘pulmonary sequestration’ by Pryce in 1946.18,19 These lesions are composed predominantly of solid lung tissue with no bronchial communication and the arterial blood supply is derived from systemic rather than pulmonary blood vessels (e.g. the aorta). There is a long-standing classification of sequestrations into intralobar and extralobar types dependent on appearance.
Congenital lobar emphysema (CLE) is characterised by hyperinflation of one lobe (rarely more), secondary to bronchial obstruction (perhaps due to a cartilage defect) with a resulting ballvalve effect.24,25 It usually affects the left and right upper lobes and tends to present early with respiratory distress, tracheal and mediastinal displacement. CLE also seems to appear relatively infrequently in the larger series of antenatally detected CTMs, suggesting that their prenatal ultrasound appearance is relatively innocuous.9
Table 1 Congenital pulmonary airway malformation: current classification.14 Type
Incidence
0
Rare
1
Common
2
Common
3
Rare
Solid
4
Rare
Large cysts
PPB, pleuropulmonary blastoma.
Cyst size and character
Large (>2 cm), can be multiple. Multiple small cysts, ‘sponge-like’
Histology
Notes
Complete failure of development beyond pseudoglandular stage. Pseudostratified ciliated columnar epithelium, interspersed with rows of mucous cells. Dilated bronchiole-like structures interspersed by simplified alveolar parenchyma. Occasional striated muscle. Bronchiolar structures are separated by small air spaces with cuboidal lining resembling late fetal lung. Peripheral and lined by alveolar or bronchiolar epithelial cells resting upon loose mesenchymal tissue.
Congenital acinar dysplasia (lethal)
Related to regressed and grade 1 PPB
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Although an old term,26 some newer features of congenital segmental emphysema (CSE) have recently been described.27 Paramalingam et al. described ten cases that were detected antenatally with early computed tomography (CT) imaging invariably showing a solid segmental appearance.27 This tended to evolve to give a hyperinflated appearance of the segment, often associated with a more centrally placed bronchocele and usually the onset of symptoms. Some authors refer to this entity as peripheral bronchial atresia28 and although this is the likeliest underlying pathology it can be difficult to demonstrate histologically and is also found in clinical cases of CCAMs, hybrids and even sequestrations.3 8. Polyalveolar lobe Polyalveolar lobe is a type of hyperplastic lung lesion in which the number of conductive airways is normal, but the numbers of alveoli per acinus are increased.29 The affected lobe, usually left upper, is enlarged and air-filled, clinically resembling CLE, but individual alveoli are not increased in size. The aetiology is obscure but partial or sporadic airway obstruction may lead to a lesser degree of hyperplasia when compared to the hyperplasia associated with laryngeal atresia. 9. Bronchogenic and foregut duplication cysts Bronchogenic cysts arise from defective development of the large airways (trachea/bronchus) and share the same origin as duplication cysts of the foregut.30e32 They appear as thick-walled (smooth muscle, occasionally cartilage) cysts lined by respiratory epithelium. Most are found in relation to the trachea and bronchi and hence present as mediastinal cysts. Occasionally detected antenatally, they may be obstructive to neighbouring viscera (e.g. oesophagus) or a focus for secondary infection. Though there are two distinct phases in management, before and after birth, the thrust of this review is directed at the life after birth. 10. Postnatal investigation and management Neonatal respiratory distress due to functional diminution in lung volume (usually CCAM but rarely CLE) is actually an uncommon mode of presentation de novo. In those countries with universal antenatal ultrasound screening programmes, these should have been detected and transferred in utero to specialist centres for delivery.9,33,34 Perhaps 10% of neonates will have symptoms shortly after birth and, following resuscitation, they should then proceed to urgent CT confirmation of the nature of the lesion and emergency resectional surgery. Substantial ventilator support or even ECMO postnatally may be required. Our systematic review suggested a mortality rate during this period of about 7%.17 11. Asymptomatic congenital thoracic malformations Most infants with antenatally detected lesions are entirely asymptomatic. However, those who may develop symptoms need to be distinguished from those whose pathology is minimal and probably will never cause harm.11 There are three possible justifications for ‘prophylactic surgery’: (i) prevention of pulmonary infection; (ii) prevention of malignancy; (iii) early surgery may be associated with better compensatory growth in the remaining lung. Some authors do adopt a ‘wait and see’ approach and have published follow-up data though this is rare.35e37 One series from Vancouver, Canada35 reported that spontaneous resolution of ‘CCAM’ occurred in 2 of 56 (4%) children in a 7-year period.
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However, few data were presented of what happened to the rest and the imaging was not convincing. A more worrying study was reported recently from Toronto, Canada36 reviewing the data from 129 children with ‘CCAM’ where 55 were managed conservatively. Synchronously, in the same institution five pleuropulmonary blastomas were diagnosed of which three were initially diagnosed as CCAM, therefore 2% overall. Though radiological review could find no distinguishing features from CCAM all of these had cysts >3 cm in diameter and none were antenatally detected. By contrast, CLE has not been associated with later malignant transformation and uncommonly causes symptoms outside of the neonatal period and some have advocated a conservative approach for this lesion.38 Of course, a conservative approach should still involve serial imaging. Unfortunately, the only one that counts is a CT scan and this involves ionising radiation. As yearly scans have been recommended by conservative advocates,35 this can be quite substantial as one authority has suggested that a single CT scan is equivalent to an extra years’ worth of exposure to normal background radiation39 and a not insubstantial risk of later cancer.40 Though newer technology, better shielding and a more focused approach will reduce the radiation dose overall it is still important to bear this in mind. As yet the alternative of magnetic resonance (MR) technology is not sufficiently detailed to replace CT in this field. The alternative, of course, is to subject any child diagnosed with a significant (however defined) lesion to excisional surgery. Stanton et al.17 reviewed 41 reports detailing 1070 patients and showed that there was about a 3% incidence of respiratory complications in those treated conservatively following antenatal detection. All were asymptomatic initially and this change occurred at a median age of 6.9 months. There was also an increased risk of both mortality (3% vs 0.3%) and morbidity (17% vs 5%) in those for whom surgery was carried out as an emergency after the onset of symptoms, compared to those for whom surgery was elective in asymptomatic cases. Given the relatively short follow-up in most of these series, the true incidence of complications is likely to be higher. As an illustration of this in one recent series from Sydney, Australia, with a longer follow-up there was a much higher incidence of complications in initially asymptomatic cases41 with 18 out of 21 developing symptoms at a median age of 2 years (range: 1 month to 13 years). 12. Conventional thoracotomy and lung resection Currently, most excisional surgery is performed using conventional open techniques. Thoracotomy should be performed using a muscle-splitting rather than muscle-cutting approach42 and, in general, lobectomy is preferred to segmentectomy or a nonanatomical wedge resection as there is a recurrence rate following the latter variations of up to 15%.43 However, if the CTM involves multiple lobes then these are better options. Preoperative identification of aberrant vessels is important and should aid vascular control before parenchymal division. Resection of ELS is usually straightforward, but especial care needs to be taken with the vasculature and typically this involves control of a large feeding vessel arising from the aorta below the diaphragm. Early postoperative complications such as atelectasis, prolonged air leak, pleural effusion, chylous effusion, pneumothorax and bronchopleural fistula are uncommon and paradoxically are seen more after segmentectomy than lobectomy. In the longer term, scoliosis and chest wall deformities are possible sequelae but their prevalence is not known and should be rare with modern musclesparing techniques.
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13. Thoracoscopy and minimally invasive resection
14.2. Malignancy risk in CCAM and bronchogenic cyst
The largest video-assisted thoracoscopic surgery (VATS) series was reported by Steven Rothenberg from Denver, Colorado. He described 97 lobectomies (56 for CCAM, 9 for CLE and 9 for sequestration) with a conversion rate of about 3% and used a single lung ventilation technique to create sufficient space.44 The main difficulties reported during thoracoscopic procedures are the safe control of major vascular structures. Although most lung pathology can be treated thoracoscopically, some lesions such as lobar emphysema can cause difficulty because of the hyperinflated lobe and difficult access in a small chest cavity.44,45 Caution is also advised in those with a history of pneumonia because of the risk of adhesions and loss of fissure anatomy. Comparative studies are few and show little difference in terms of outcome, apart from arguably better cosmesis in the thoracoscopic group.44e46
Both CCAM and bronchogenic cysts have a pre-malignant potential although the risk of transformation and the overall prevalence are not known. The relationship is clear and should always be borne in mind during counselling. Pleuropulmonary blastomas (PPBs) are rare malignant tumours occurring in children that appear to arise from pleuropulmonary germ cells with some regarding it as the pulmonary dysontogenetic equivalent to Wilms’ tumour in the kidney and neuroblastoma in the adrenal gland. Furthermore what are now referred to as PPB have formerly been termed embryoma of the lung, pulmonary blastoma, pulmonary sarcoma, embryonal sarcoma, pulmonary rhabdomyosarcoma, embryonal rhabdomyosarcoma, and malignant mesenchymoma.61e68 PPB can be subclassified into three grades based on gross morphological appearance and therefore there are grade 1 PPB tumours that are exclusively cystic; grade III tumours that are predominantly solid; and grade II tumours that have both solid and cystic components. There is also histological overlap and therefore potential diagnostic confusion between type 4 CCAM and grade 1 PPB.15 Up to 40% of PPB tumours will show clinical or radiological evidence of cyst formation69 and it is with this group of lung neoplasms that pre-existing CCAM has been predominantly reported.61e68 Typically affected children are aged <5 years but rarely antenatal presentation has also been described both for de-novo and CCAM-associated grade 1 PPB.70 Bronchioloalveolar carcinoma (BAC) derived from type II pneumocytes, is a subgroup of adenocarcinoma, and usually occurs in patients in their 50s and 60s. However, there are several reports of it arising in pre-existing type 1 CCAM, with the average age for this being young adulthood15,71e74 but with some even occurring during childhood,15,75e77 and therefore strongly suggesting malignant transformation of underlying CCAM. The other lesion within our umbrella term of CTM which has a definite relationship with later malignancy is the bronchogenic cyst. Here, malignant transformation has been described leading to squamous cell carcinoma78 and BAC79,80 from the lining epithelial cells to leiomyosarcoma from the wall.81 Typically this occurs during adulthood.79e82
14. Long term outcomes 14.1. Lung growth and lung function The long term respiratory outcome after surgery depends on the extent of lung resection. The potential for alveolar growth and thus the ability of infants to replace lost lung parenchyma is thought to decrease with age with developmental maturity of the anatomical lung unit achieved at about two years of age.47e50 Although it is believed that lung resection at an early age allows for better compensatory lung growth the evidence is scanty, and studies that are now quite dated (where the lesions resected were almost certainly symptomatic). They usually employed lung function as a surrogate to assess compensatory lung growth and have produced conflicting results. One study reported reduced lung volumes and diffusing capacity, approximately by the amount predictable from the size of lung resected.51 Other authors found evidence for some compensatory growth, but no normalisation of physiological measurements,52 and another group reported complete normalisation of lung volumes after lobectomy for CLE in infancy.53 Larger lung volumes than expected from the amount of remaining lung tissue, however, do not necessarily indicate the presence of adequate lung growth in the remaining lung; the mild-to-moderate elevation of residual volume (RV) and functional residual capacity (FRC) commonly found after lobectomy suggests that overexpansion of the residual lung contributes to compensation for volume loss.54e56 One study found diminished perfusion in the resected area supporting this hypothesis.56 More recent follow-up studies looking at the specific effect of age at surgery have been conflicting. Nakajima et al. showed more compensatory lung growth in those aged <4 years at surgery.57 However, Keijzer et al. in a retrospective study showed that age at lobectomy (surgery <2 versus 2 years of age) did not influence forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1) when assessed at a mean age of 10 years.58 Some 30 years ago, in a small study, normal growth rate of functional lung tissue could be demonstrated for both children after surgical resection of CLE and children in whom this malformation had been managed expectantly.59 Both groups had reduced FVC, large trapped gas volumes and reduced forced expiratory flows at low lung volumes. Thus, it appears that the growth of the remaining lung is not hampered by a non-resected cystic lesion, or space-occupying hyperinflated lobe. Another small study in CCAM patients evaluated outcome and lung function in the first year of life. The authors reported mild airway obstruction without respiratory symptoms, with no difference between patients treated conservatively and those treated surgically.60 Clearly, more studies are needed to resolve this issue.
15. Conclusions Although CTMs are still relatively uncommon they do have the potential to cause significant morbidity and mortality. Proper identification of those infants likely to develop early symptoms is a key part of antenatal detection so that they can be born in an appropriate environment for surgery and respiratory care. Equally important is to recognise that the majority will be asymptomatic but need full radiological evaluation whatever the last antenatal ultrasound report suggested, and these also deserve consideration for surgical intervention and removal or a conscientious programme of radiological surveillance.
Practice points Antenatal detection of congenital parenchymal abnormalities is the start of the diagnostic process, not the end. In-utero transfer of large lesions identified antenatally. Early investigation of even asymptomatic infants with CT scan. Surgical removal is a reasonable response for significant pre-symptom lesions.
M. Davenport, E. Eber / Seminars in Fetal & Neonatal Medicine 17 (2012) 99e104
Research directions Embryological basis for congenital parenchymal malformations. Definition of malignant potential of congenital cystic adenomatoid malformations.
Conflict of interest statement None declared. Funding sources None.
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61. Priest JR, Williams GM, Hill DA, Dehner LP, Jaffé A. Pulmonary cysts in early childhood and the risk of malignancy. Pediatr Pulmonol 2009;44:14e30. 62. Ueda K, Grupps R, Unger F. Rhabdomyosarcoma of lung arising in congenital cystic adenomatoid malformation. Cancer 1977;40:383e8. 63. Shariff S, Thomas JA, Shetty N, D’Cunha S. Primary pulmonary rhabdomyosarcoma in a child, with a review of literature. J Surg Oncol 1988;38:261e4. 64. Murphy JJ. Rhabdomyosarcoma arising within congenital pulmonary cysts: report of three cases. J Pediatr Surg 1992;27:1364e7. 65. Federici S, Domenichelli V, Tani G, et al. Pleuropulmonary blastoma in congenital cystic adenomatoid malformation: report of a case. Eur J Pediatr Surg 2001;11:196e9. 66. Özcan C, Celik A, Ural Z, Veral A, Kandiloglu G, Balik E. Primary pulmonary rhabdomyosarcoma arising within cystic adenomatoid malformation: a case report and review of the literature. J Pediatr Surg 2001;36:1062e5. 67. Papagiannopoulos K, Hughes S, Nicholson AG, Goldstraw P. Cystic lung lesions in the pediatric and adult population: surgical experience at the Brompton Hospital. Ann Thorac Surg 2002;73:1594e8. 68. Pai S, Eng HL, Lee SY, Hsiao CC, Huang WT, Huang SC. Rhabdomyosarcoma arising within congenital cystic adenomatoid malformation. Pediatr Blood Cancer 2005;45:841e5. 69. Priest JR, McDermott MB, Bhatia S, Watterson J, Manivel JC, Dehner LP. Pleuropulmonary blastoma: a clinicopathologic study of 50 cases. Cancer 1997;80:147e61. 70. Miniatib DN, Chintagumpalac M, Langston C, et al. Prenatal presentation and outcome of children with pleuropulmonary blastoma. J Pediatr Surg 2006;41:66e71. 71. Prichard MG, Brown PJ, Sterret GF. Bronchioloalveolar carcinoma arising in longstanding lung cysts. Thorax 1984;39:545e9.
72. Sheffield EA, Addis BJ, Corrin B, McCabe MM. Epithelial hyperplasia and malignant change in congenital lung cysts. J Clin Pathol 1987;40:612e4. 73. Benjamin DR, Cahill JL. Bronchioloalveolar carcinoma of the lung and congenital cystic adenomatoid malformation. Am J Clin Pathol 1991;95:889e92. 74. Ribet ME, Copin MC, Soots JG, Gosselin BH. Bronchioloalveolar carcinoma and congenital cystic adenomatoid malformation. Ann Thorac Surg 1995;60:1126e8. 75. Granata C, Gambini C, Balducci T, et al. Bronchioloalveolar carcinoma arising in congenital cystic adenomatoid malformation in a child: a case report and review of malignancies originating in congenital cystic adenomatoid malformation. Pediatr Pulmonol 1998;25:62e6. 76. Ioachimescu OC, Mehta AC. From cystic pulmonary airway malformation, to bronchioloalveolar carcinoma and adenocarcinoma of the lung. Eur Respir J 2005;26:1181e7. 77. Kaslovsky RA, Purdy S, Dangman BC, McKenna BJ, Brien T, Ilves R. Bronchioloalveolar carcinoma in a child with congenital cystic adenomatoid malformation. Chest 1997;112:548e51. 78. Cuypers P, De Leyn P, Cappelle L, Verougstraete L, Demedts M, Deneffe G. Bronchogenic cysts: a review of 20 cases. Eur J Cardiothorac Surg 1996;10:393e6. 79. Endo C, Imai T, Nakagawa H, Ebina A, Kaimori M. Bronchioloalveolar carcinoma arising in a bronchogenic cyst. Ann Thorac Surg 2000;69:933e5. 80. de Perrot M, Pache JC, Spiliopoulos A. Carcinoma arising in congenital lung cysts. Thorac Cardiovasc Surg 2001;49:184e5. 81. Bernheim J, Griffel B, Versano S. Bruderman. Mediastinal leiomyosarcoma in the wall of a bronchial cyst (letter). Arch Pathol Lab Med 1980;104:221. 82. Jakopovic M, Slobodnjak Z, Krizanac S, Samarzija M. Large cell carcinoma arising in bronchogenic cyst. J Thorac Cardiovasc Surg 2005;130:610e2.
Contents lists available at SciVerse ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Long term respiratory outcomes of congenital thoracic malformations Mark Davenport a, *, Ernst Eber b a b
Department of Paediatric Surgery, King’s College Hospital, London, UK Respiratory and Allergic Disease Division, Department of Paediatrics, Medical University of Graz, Graz, Austria
s u m m a r y Keywords: Bronchopulmonary sequestration Congenital cystic adenomatoid malformation Congenital lobar emphysema Lobectomy Congenital thoracic malformation Malignancy change
The advent of universal antenatal ultrasonography in many countries has revealed the full spectrum of congenital thoracic malformations (CTMs) and presented clinicians with a number of practical dilemmas to do with diagnosis and management. We present a review of the most common forms of CTMs, including congenital cystic adenomatoid malformation, bronchopulmonary sequestration, and lobar and segmental emphysema. Ó 2012 Published by Elsevier Ltd.
1. Introduction The term congenital thoracic malformation (CTM) is an umbrella phrase for developmental lesions present at birth derived from lung and its adnexal tissue, but which confers no actual histological meaning or implied derivation. Included under this umbrella are true pulmonary parenchymal lesions such as the various types of congenital cystic adenomatoid malformation (CCAM), extra- and intralobar bronchopulmonary sequestration and congenital lobar and segmental emphysemas together with less common entities such as foregut duplication and bronchogenic cysts. The characteristics of each will be outlined later. The aim of this review is to summarise our current understanding of such lesions with a focus on what may happen outside of infancy to those who have been treated to the usual therapy e surgical resection e and those where a more conservative approach has been taken.
worked out as an incidence of 4.44 per 10,000 fetuses and translated to an incidence of 3.52 per 10,000 live births. During that year the estimated incidence of CCAM was 0.7 per 10,000 live births, or about one-quarter of all CTMs. 3. Common origin of congenital thoracic malformations It is thought that lung parenchymal malformations although superficially heterogeneous in appearance, share a common embryological origin and have significant overlap. Although not an original concept, Langston re-proposed that disordered parenchymal development might be attributed to in-utero airway obstruction,2 with the level, timing and the completeness of the obstruction producing different patterns of lung malformation. There is histological evidence for peripheral bronchial atresia/ stenosis in many apparently separate entities,3 but the mode and timing of these events is still speculative.
2. Incidence
4. Congenital cystic adenomatoid malformation (CCAM)
The European Surveillance of Congenital Anomalies (EUROCAT) was established in 1979 with the aim of providing a network of population-based registers for the epidemiological surveillance of congenital anomalies. Data have been collected from 43 European registries in 20 European countries with an estimated capture of about 29% of Europe’s birth population.1 The EUROCAT database showed that in 2008, there were 222 fetuses with a CTM, which
The first clinical report by Ch’in and Tang of what was termed congenital adenomatoid malformation appeared in 1947.4 In 1975, Garrett et al.5 first reported the antenatal detection of a CCAM using greyscale ultrasound which heralded the current era in which >90% of lesions are detected in antenatal screening programmes. Although early reports in the obstetric literature6e8 were characterised by large lesions, a marked association with other abnormalities and a poor prognosis, we now realise that the majority are relatively small lesions, which are usually asymptomatic, at least in early postnatal life.9,10 CCAMs appear to be derived from the proliferation of peripheral bronchiolar tissue at the expense of alveolar tissues with a single
* Corresponding author. Address: Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel.: þ44 (0) 203 299 3350; fax: þ44 (0) 203 299 4021. E-mail address: [email protected] (M. Davenport). 1744-165X/$ e see front matter Ó 2012 Published by Elsevier Ltd. doi:10.1016/j.siny.2012.01.011
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lobe affected in >95% of cases with no particular preference for side,9e12 though there is a predilection for the basal lobes. Bilateral lesions are uncommon (<3%) and usually have a poor prognosis.7 The original Stocker classification13 was based on postnatal histology and originally divided CCAMs into three types (1, 2 and 3). Subsequently the rarer types 0 and 4 were also proposed, expanding the classification so that type 0 was an essentially tracheobronchial defect (also known as acinar dysplasia) and characterised by firm small lungs with a bronchial airway; and type 4 an entirely alveolar defect occurring at the periphery of the lungs.14 It is noteworthy that only types 1e3 are adenomatoid and only types 1, 2 and 4 are cystic and it is also noteworthy that Stocker himself proposed a new name for such lesions e congenital pulmonary airway malformation (CPAM) e although whether this will replace CCAM only time will tell. Type 4 CCAM is a more controversial entity as its features overlap with type 1 pleuropulmonary blastoma, the only distinguishing feature being a lack of blastema in type 4 CCAM.15 The current characteristics of the classification are summarized in Table 1.
4.1. Clinical features As befits the complexity and variation in pathology, the nature of clinical features also varies considerably. In fetal life, large spaceoccupying lesions (of whatever histology) may cause mediastinal shift, impairment of venous return and hydrops leading to fetal demise typically in the third trimester.6,7 A proportion (<20%) will cause early respiratory distress within the first month after birth requiring early surgical excision.8e10,16 The remainder are asymptomatic but are prone to develop infection (pneumonia, lung abscess, empyema, etc.) and occasionally cyst rupture leading to pneumothorax. A recent systematic literature review has suggested that the median age of symptom development in this group was about 10 months.17 The malignant potential of such lesions will be addressed in detail later.
Intralobar sequestration (ILS): often embedded in normal parenchyma and covered by visceral pleura in continuity with the normal lung. The venous drainage is usually into the pulmonary vein. Extralobar sequestration (ELS): invariably solid with its own separate pleural covering, separate from the normal lung. Most sequestrations are medio-basal in location (left > right) and about 10% are actually located below the diaphragm.20 ELS may be found in association with diaphragmatic hernias, but other anomalies are less common (e.g. chest wall anomalies, vertebral deformities, hindgut duplications and congenital heart disease). Very large sequestrations can act as space-occupying lesions and diminish respiratory reserve but most appear silent. A peculiar complication, not seen with CCAM, is high output cardiac failure associated with the sequestration’s redundant circulation and occasionally massive left-to-left shunt. Some of these will present during the antenatal period21 with hydrothorax and pleural effusion, requiring in-utero drainage. A novel approach to some obvious echogenic lesions (usually thought to be sequestrations) has been in-utero laser ablation.22 6. Hybrid lesions This term refers to the overlap between CCAM and sequestration.23 Several surgical series have shown that some lesions do not fit neatly into the above two categories and are usually labelled hybrids.9 Features might include: Anatomical ELS but with histological appearance more compatible with CCAM; ELS and CCAM occurring in the same patient; Obvious CCAM lesions in a lobe but with an accessory systemic blood supply.
7. Lobar and segmental emphysema 5. Bronchopulmonary sequestrations Bronchopulmonary sequestrations were first termed ‘accessory pulmonary lobes’ by Rokitansky in 1861, but later renamed ‘pulmonary sequestration’ by Pryce in 1946.18,19 These lesions are composed predominantly of solid lung tissue with no bronchial communication and the arterial blood supply is derived from systemic rather than pulmonary blood vessels (e.g. the aorta). There is a long-standing classification of sequestrations into intralobar and extralobar types dependent on appearance.
Congenital lobar emphysema (CLE) is characterised by hyperinflation of one lobe (rarely more), secondary to bronchial obstruction (perhaps due to a cartilage defect) with a resulting ballvalve effect.24,25 It usually affects the left and right upper lobes and tends to present early with respiratory distress, tracheal and mediastinal displacement. CLE also seems to appear relatively infrequently in the larger series of antenatally detected CTMs, suggesting that their prenatal ultrasound appearance is relatively innocuous.9
Table 1 Congenital pulmonary airway malformation: current classification.14 Type
Incidence
0
Rare
1
Common
2
Common
3
Rare
Solid
4
Rare
Large cysts
PPB, pleuropulmonary blastoma.
Cyst size and character
Large (>2 cm), can be multiple. Multiple small cysts, ‘sponge-like’
Histology
Notes
Complete failure of development beyond pseudoglandular stage. Pseudostratified ciliated columnar epithelium, interspersed with rows of mucous cells. Dilated bronchiole-like structures interspersed by simplified alveolar parenchyma. Occasional striated muscle. Bronchiolar structures are separated by small air spaces with cuboidal lining resembling late fetal lung. Peripheral and lined by alveolar or bronchiolar epithelial cells resting upon loose mesenchymal tissue.
Congenital acinar dysplasia (lethal)
Related to regressed and grade 1 PPB
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Although an old term,26 some newer features of congenital segmental emphysema (CSE) have recently been described.27 Paramalingam et al. described ten cases that were detected antenatally with early computed tomography (CT) imaging invariably showing a solid segmental appearance.27 This tended to evolve to give a hyperinflated appearance of the segment, often associated with a more centrally placed bronchocele and usually the onset of symptoms. Some authors refer to this entity as peripheral bronchial atresia28 and although this is the likeliest underlying pathology it can be difficult to demonstrate histologically and is also found in clinical cases of CCAMs, hybrids and even sequestrations.3 8. Polyalveolar lobe Polyalveolar lobe is a type of hyperplastic lung lesion in which the number of conductive airways is normal, but the numbers of alveoli per acinus are increased.29 The affected lobe, usually left upper, is enlarged and air-filled, clinically resembling CLE, but individual alveoli are not increased in size. The aetiology is obscure but partial or sporadic airway obstruction may lead to a lesser degree of hyperplasia when compared to the hyperplasia associated with laryngeal atresia. 9. Bronchogenic and foregut duplication cysts Bronchogenic cysts arise from defective development of the large airways (trachea/bronchus) and share the same origin as duplication cysts of the foregut.30e32 They appear as thick-walled (smooth muscle, occasionally cartilage) cysts lined by respiratory epithelium. Most are found in relation to the trachea and bronchi and hence present as mediastinal cysts. Occasionally detected antenatally, they may be obstructive to neighbouring viscera (e.g. oesophagus) or a focus for secondary infection. Though there are two distinct phases in management, before and after birth, the thrust of this review is directed at the life after birth. 10. Postnatal investigation and management Neonatal respiratory distress due to functional diminution in lung volume (usually CCAM but rarely CLE) is actually an uncommon mode of presentation de novo. In those countries with universal antenatal ultrasound screening programmes, these should have been detected and transferred in utero to specialist centres for delivery.9,33,34 Perhaps 10% of neonates will have symptoms shortly after birth and, following resuscitation, they should then proceed to urgent CT confirmation of the nature of the lesion and emergency resectional surgery. Substantial ventilator support or even ECMO postnatally may be required. Our systematic review suggested a mortality rate during this period of about 7%.17 11. Asymptomatic congenital thoracic malformations Most infants with antenatally detected lesions are entirely asymptomatic. However, those who may develop symptoms need to be distinguished from those whose pathology is minimal and probably will never cause harm.11 There are three possible justifications for ‘prophylactic surgery’: (i) prevention of pulmonary infection; (ii) prevention of malignancy; (iii) early surgery may be associated with better compensatory growth in the remaining lung. Some authors do adopt a ‘wait and see’ approach and have published follow-up data though this is rare.35e37 One series from Vancouver, Canada35 reported that spontaneous resolution of ‘CCAM’ occurred in 2 of 56 (4%) children in a 7-year period.
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However, few data were presented of what happened to the rest and the imaging was not convincing. A more worrying study was reported recently from Toronto, Canada36 reviewing the data from 129 children with ‘CCAM’ where 55 were managed conservatively. Synchronously, in the same institution five pleuropulmonary blastomas were diagnosed of which three were initially diagnosed as CCAM, therefore 2% overall. Though radiological review could find no distinguishing features from CCAM all of these had cysts >3 cm in diameter and none were antenatally detected. By contrast, CLE has not been associated with later malignant transformation and uncommonly causes symptoms outside of the neonatal period and some have advocated a conservative approach for this lesion.38 Of course, a conservative approach should still involve serial imaging. Unfortunately, the only one that counts is a CT scan and this involves ionising radiation. As yearly scans have been recommended by conservative advocates,35 this can be quite substantial as one authority has suggested that a single CT scan is equivalent to an extra years’ worth of exposure to normal background radiation39 and a not insubstantial risk of later cancer.40 Though newer technology, better shielding and a more focused approach will reduce the radiation dose overall it is still important to bear this in mind. As yet the alternative of magnetic resonance (MR) technology is not sufficiently detailed to replace CT in this field. The alternative, of course, is to subject any child diagnosed with a significant (however defined) lesion to excisional surgery. Stanton et al.17 reviewed 41 reports detailing 1070 patients and showed that there was about a 3% incidence of respiratory complications in those treated conservatively following antenatal detection. All were asymptomatic initially and this change occurred at a median age of 6.9 months. There was also an increased risk of both mortality (3% vs 0.3%) and morbidity (17% vs 5%) in those for whom surgery was carried out as an emergency after the onset of symptoms, compared to those for whom surgery was elective in asymptomatic cases. Given the relatively short follow-up in most of these series, the true incidence of complications is likely to be higher. As an illustration of this in one recent series from Sydney, Australia, with a longer follow-up there was a much higher incidence of complications in initially asymptomatic cases41 with 18 out of 21 developing symptoms at a median age of 2 years (range: 1 month to 13 years). 12. Conventional thoracotomy and lung resection Currently, most excisional surgery is performed using conventional open techniques. Thoracotomy should be performed using a muscle-splitting rather than muscle-cutting approach42 and, in general, lobectomy is preferred to segmentectomy or a nonanatomical wedge resection as there is a recurrence rate following the latter variations of up to 15%.43 However, if the CTM involves multiple lobes then these are better options. Preoperative identification of aberrant vessels is important and should aid vascular control before parenchymal division. Resection of ELS is usually straightforward, but especial care needs to be taken with the vasculature and typically this involves control of a large feeding vessel arising from the aorta below the diaphragm. Early postoperative complications such as atelectasis, prolonged air leak, pleural effusion, chylous effusion, pneumothorax and bronchopleural fistula are uncommon and paradoxically are seen more after segmentectomy than lobectomy. In the longer term, scoliosis and chest wall deformities are possible sequelae but their prevalence is not known and should be rare with modern musclesparing techniques.
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13. Thoracoscopy and minimally invasive resection
14.2. Malignancy risk in CCAM and bronchogenic cyst
The largest video-assisted thoracoscopic surgery (VATS) series was reported by Steven Rothenberg from Denver, Colorado. He described 97 lobectomies (56 for CCAM, 9 for CLE and 9 for sequestration) with a conversion rate of about 3% and used a single lung ventilation technique to create sufficient space.44 The main difficulties reported during thoracoscopic procedures are the safe control of major vascular structures. Although most lung pathology can be treated thoracoscopically, some lesions such as lobar emphysema can cause difficulty because of the hyperinflated lobe and difficult access in a small chest cavity.44,45 Caution is also advised in those with a history of pneumonia because of the risk of adhesions and loss of fissure anatomy. Comparative studies are few and show little difference in terms of outcome, apart from arguably better cosmesis in the thoracoscopic group.44e46
Both CCAM and bronchogenic cysts have a pre-malignant potential although the risk of transformation and the overall prevalence are not known. The relationship is clear and should always be borne in mind during counselling. Pleuropulmonary blastomas (PPBs) are rare malignant tumours occurring in children that appear to arise from pleuropulmonary germ cells with some regarding it as the pulmonary dysontogenetic equivalent to Wilms’ tumour in the kidney and neuroblastoma in the adrenal gland. Furthermore what are now referred to as PPB have formerly been termed embryoma of the lung, pulmonary blastoma, pulmonary sarcoma, embryonal sarcoma, pulmonary rhabdomyosarcoma, embryonal rhabdomyosarcoma, and malignant mesenchymoma.61e68 PPB can be subclassified into three grades based on gross morphological appearance and therefore there are grade 1 PPB tumours that are exclusively cystic; grade III tumours that are predominantly solid; and grade II tumours that have both solid and cystic components. There is also histological overlap and therefore potential diagnostic confusion between type 4 CCAM and grade 1 PPB.15 Up to 40% of PPB tumours will show clinical or radiological evidence of cyst formation69 and it is with this group of lung neoplasms that pre-existing CCAM has been predominantly reported.61e68 Typically affected children are aged <5 years but rarely antenatal presentation has also been described both for de-novo and CCAM-associated grade 1 PPB.70 Bronchioloalveolar carcinoma (BAC) derived from type II pneumocytes, is a subgroup of adenocarcinoma, and usually occurs in patients in their 50s and 60s. However, there are several reports of it arising in pre-existing type 1 CCAM, with the average age for this being young adulthood15,71e74 but with some even occurring during childhood,15,75e77 and therefore strongly suggesting malignant transformation of underlying CCAM. The other lesion within our umbrella term of CTM which has a definite relationship with later malignancy is the bronchogenic cyst. Here, malignant transformation has been described leading to squamous cell carcinoma78 and BAC79,80 from the lining epithelial cells to leiomyosarcoma from the wall.81 Typically this occurs during adulthood.79e82
14. Long term outcomes 14.1. Lung growth and lung function The long term respiratory outcome after surgery depends on the extent of lung resection. The potential for alveolar growth and thus the ability of infants to replace lost lung parenchyma is thought to decrease with age with developmental maturity of the anatomical lung unit achieved at about two years of age.47e50 Although it is believed that lung resection at an early age allows for better compensatory lung growth the evidence is scanty, and studies that are now quite dated (where the lesions resected were almost certainly symptomatic). They usually employed lung function as a surrogate to assess compensatory lung growth and have produced conflicting results. One study reported reduced lung volumes and diffusing capacity, approximately by the amount predictable from the size of lung resected.51 Other authors found evidence for some compensatory growth, but no normalisation of physiological measurements,52 and another group reported complete normalisation of lung volumes after lobectomy for CLE in infancy.53 Larger lung volumes than expected from the amount of remaining lung tissue, however, do not necessarily indicate the presence of adequate lung growth in the remaining lung; the mild-to-moderate elevation of residual volume (RV) and functional residual capacity (FRC) commonly found after lobectomy suggests that overexpansion of the residual lung contributes to compensation for volume loss.54e56 One study found diminished perfusion in the resected area supporting this hypothesis.56 More recent follow-up studies looking at the specific effect of age at surgery have been conflicting. Nakajima et al. showed more compensatory lung growth in those aged <4 years at surgery.57 However, Keijzer et al. in a retrospective study showed that age at lobectomy (surgery <2 versus 2 years of age) did not influence forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1) when assessed at a mean age of 10 years.58 Some 30 years ago, in a small study, normal growth rate of functional lung tissue could be demonstrated for both children after surgical resection of CLE and children in whom this malformation had been managed expectantly.59 Both groups had reduced FVC, large trapped gas volumes and reduced forced expiratory flows at low lung volumes. Thus, it appears that the growth of the remaining lung is not hampered by a non-resected cystic lesion, or space-occupying hyperinflated lobe. Another small study in CCAM patients evaluated outcome and lung function in the first year of life. The authors reported mild airway obstruction without respiratory symptoms, with no difference between patients treated conservatively and those treated surgically.60 Clearly, more studies are needed to resolve this issue.
15. Conclusions Although CTMs are still relatively uncommon they do have the potential to cause significant morbidity and mortality. Proper identification of those infants likely to develop early symptoms is a key part of antenatal detection so that they can be born in an appropriate environment for surgery and respiratory care. Equally important is to recognise that the majority will be asymptomatic but need full radiological evaluation whatever the last antenatal ultrasound report suggested, and these also deserve consideration for surgical intervention and removal or a conscientious programme of radiological surveillance.
Practice points Antenatal detection of congenital parenchymal abnormalities is the start of the diagnostic process, not the end. In-utero transfer of large lesions identified antenatally. Early investigation of even asymptomatic infants with CT scan. Surgical removal is a reasonable response for significant pre-symptom lesions.
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Research directions Embryological basis for congenital parenchymal malformations. Definition of malignant potential of congenital cystic adenomatoid malformations.
Conflict of interest statement None declared. Funding sources None.
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